3DAL
108-409: 639 12142 ENSG00000057657 ENSMUSG00000038151 O75626 Q60636 NM_001198 NM_182907 NM_007548 NP_001189 NP_878911 NP_001392862 NP_001392863 NP_001392864 NP_001392865 PR domain zinc finger protein 1 , or B lymphocyte-induced maturation protein-1 ( BLIMP-1 ), is a protein in humans encoded by the gene PRDM1 located on chromosome 6q21. BLIMP-1
216-516: A carboxyl group, and a variable side chain are bonded . Only proline differs from this basic structure as it contains an unusual ring to the N-end amine group, which forces the CO–NH amide moiety into a fixed conformation. The side chains of the standard amino acids, detailed in the list of standard amino acids , have a great variety of chemical structures and properties; it is the combined effect of all of
324-470: A gene may be duplicated before it can mutate freely. However, this can also lead to complete loss of gene function and thus pseudo-genes . More commonly, single amino acid changes have limited consequences although some can change protein function substantially, especially in enzymes . For instance, many enzymes can change their substrate specificity by one or a few mutations. Changes in substrate specificity are facilitated by substrate promiscuity , i.e.
432-492: A cell lineage determinant in monocytes , inducing their differentiation into DCs and macrophages . It is speculated to have the similar effects in vivo. In addition, BLIMP-1 also suppressed myeloid cells from differentiating into granulocytes , which includes eosinophil, basophil, and neutrophils. The role of BLIMP-1 in DCs and macrophages development is a matter of interest because analysis have suggested that DCs, rather than B-cells,
540-450: A characteristic protein fold structure that binds DNA to regulate expression of target genes. Homeodomain proteins regulate gene expression and cell differentiation during early embryonic development, thus mutations in homeobox genes can cause developmental disorders. Homeosis is a term coined by William Bateson to describe the outright replacement of a discrete body part with another body part, e.g. antennapedia —replacement of
648-552: A combination of sequence, structure and function, and they can be combined in many different ways. In an early study of 170,000 proteins, about two-thirds were assigned at least one domain, with larger proteins containing more domains (e.g. proteins larger than 600 amino acids having an average of more than 5 domains). Most proteins consist of linear polymers built from series of up to 20 different L -α- amino acids. All proteinogenic amino acids possess common structural features, including an α-carbon to which an amino group,
756-468: A common eukaryotic ancestry for TALE and non-TALE homeodomain proteins. The Hox genes in humans are organized in four chromosomal clusters: ParaHox genes are analogously found in four areas. They include CDX1 , CDX2 , CDX4 ; GSX1 , GSX2 ; and PDX1 . Other genes considered Hox-like include EVX1 , EVX2 ; GBX1 , GBX2 ; MEOX1 , MEOX2 ; and MNX1 . The NK-like (NKL) genes, some of which are considered "MetaHox", are grouped with Hox-like genes into
864-403: A defined conformation . Proteins can interact with many types of molecules, including with other proteins , with lipids , with carbohydrates , and with DNA . It has been estimated that average-sized bacteria contain about 2 million proteins per cell (e.g. E. coli and Staphylococcus aureus ). Smaller bacteria, such as Mycoplasma or spirochetes contain fewer molecules, on
972-834: A detailed review of the vegetable proteins at the Connecticut Agricultural Experiment Station . Then, working with Lafayette Mendel and applying Liebig's law of the minimum , which states that growth is limited by the scarcest resource, to the feeding of laboratory rats, the nutritionally essential amino acids were established. The work was continued and communicated by William Cumming Rose . The difficulty in purifying proteins in large quantities made them very difficult for early protein biochemists to study. Hence, early studies focused on proteins that could be purified in large quantities, including those of blood, egg whites, and various toxins, as well as digestive and metabolic enzymes obtained from slaughterhouses. In
1080-467: A fine-tuned and contextual rheostat of the immune system, BLIMP-1 up- or down-regulates immune responses depending on the precise scenarios. BLIMP-1 is highly expressed in exhausted T-cells – clones of dysfunctional T-cells with diminished functions due to chronic immune response against cancer, viral infections, or organ transplant. As a potent repressor of beta-interferon (IFN-β) , BLIMP-1 competes for interferon regulatory factors (IRF) binding sites in
1188-428: A homeobox and a paired domain that also binds DNA to increase binding specificity, though some Pax genes have lost all or part of the homeobox sequence. Pax genes function in embryo segmentation , nervous system development, generation of the frontal eye fields , skeletal development, and formation of face structures. Pax 6 is a master regulator of eye development, such that the gene is necessary for development of
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#17330861178711296-644: A large ANTP-like group. Humans have a "distal-less homeobox" family : DLX1 , DLX2 , DLX3 , DLX4 , DLX5 , and DLX6 . Dlx genes are involved in the development of the nervous system and of limbs. They are considered a subset of the NK-like genes. Human TALE (Three Amino acid Loop Extension) homeobox genes for an "atypical" homeodomain consist of 63 rather than 60 amino acids: IRX1 , IRX2 , IRX3 , IRX4 , IRX5 , IRX6 ; MEIS1 , MEIS2 , MEIS3 ; MKX ; PBX1 , PBX2 , PBX3 , PBX4 ; PKNOX1 , PKNOX2 ; TGIF1 , TGIF2 , TGIF2LX , TGIF2LY . In addition, humans have
1404-478: A little ambiguous and can overlap in meaning. Protein is generally used to refer to the complete biological molecule in a stable conformation , whereas peptide is generally reserved for a short amino acid oligomers often lacking a stable 3D structure. But the boundary between the two is not well defined and usually lies near 20–30 residues. Polypeptide can refer to any single linear chain of amino acids, usually regardless of length, but often implies an absence of
1512-452: A more posterior one. Famous examples are Antennapedia and bithorax in Drosophila , which can cause the development of legs instead of antennae and the development of a duplicated thorax, respectively. In vertebrates, the four paralog clusters are partially redundant in function, but have also acquired several derived functions. For example, HoxA and HoxD specify segment identity along
1620-410: A particular cell or cell type is known as its proteome . The chief characteristic of proteins that also allows their diverse set of functions is their ability to bind other molecules specifically and tightly. The region of the protein responsible for binding another molecule is known as the binding site and is often a depression or "pocket" on the molecular surface. This binding ability is mediated by
1728-517: A preference for the DNA sequence 5'-TAAT-3'; sequence-independent binding occurs with significantly lower affinity. The specificity of a single homeodomain protein is usually not enough to recognize specific target gene promoters, making cofactor binding an important mechanism for controlling binding sequence specificity and target gene expression. To achieve higher target specificity, homeodomain proteins form complexes with other transcription factors to recognize
1836-500: A protein carries out its function: for example, enzyme kinetics studies explore the chemical mechanism of an enzyme's catalytic activity and its relative affinity for various possible substrate molecules. By contrast, in vivo experiments can provide information about the physiological role of a protein in the context of a cell or even a whole organism . In silico studies use computational methods to study proteins. Proteins may be purified from other cellular components using
1944-411: A protein is defined by the sequence of a gene, which is encoded in the genetic code . In general, the genetic code specifies 20 standard amino acids; but in certain organisms the genetic code can include selenocysteine and—in certain archaea — pyrrolysine . Shortly after or even during synthesis, the residues in a protein are often chemically modified by post-translational modification , which alters
2052-539: A protein that fold into distinct structural units. Domains usually also have specific functions, such as enzymatic activities (e.g. kinase ) or they serve as binding modules (e.g. the SH3 domain binds to proline-rich sequences in other proteins). Short amino acid sequences within proteins often act as recognition sites for other proteins. For instance, SH3 domains typically bind to short PxxP motifs (i.e. 2 prolines [P], separated by two unspecified amino acids [x], although
2160-522: A result of chronic immune activations, commonly caused by viral infection (e.g. HIV), cancer, or organ transplant. High expression of BLIMP-1 in Tc and Th cells is associated with the transcription of receptors inhibiting immune responses, though it is unclear whether the relation between BLIMP-1 expression and T-cell exhaustion is causal or just associative. BLIMP-1 helps the production of short-lived effector T cells and clonally exhausted T cells. It also helps with
2268-486: A role in biological recognition phenomena involving cells and proteins. Receptors and hormones are highly specific binding proteins. Transmembrane proteins can also serve as ligand transport proteins that alter the permeability of the cell membrane to small molecules and ions. The membrane alone has a hydrophobic core through which polar or charged molecules cannot diffuse . Membrane proteins contain internal channels that allow such molecules to enter and exit
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#17330861178712376-406: A series of purification steps may be necessary to obtain protein sufficiently pure for laboratory applications. To simplify this process, genetic engineering is often used to add chemical features to proteins that make them easier to purify without affecting their structure or activity. Here, a "tag" consisting of a specific amino acid sequence, often a series of histidine residues (a " His-tag "),
2484-422: A single ANTP-class homeobox gene. Gene duplication followed by neofunctionalization is responsible for the many homeobox genes found in eukaryotes. Comparison of homeobox genes and gene clusters has been used to understand the evolution of genome structure and body morphology throughout metazoans. Hox genes are the most commonly known subset of homeobox genes. They are essential metazoan genes that determine
2592-503: A so-called helix-turn-helix (HTH) structure, where the two alpha helices are connected by a short loop region. The N-terminal two helices of the homeodomain are antiparallel and the longer C-terminal helix is roughly perpendicular to the axes established by the first two. It is this third helix that interacts directly with DNA via a number of hydrogen bonds and hydrophobic interactions, as well as indirect interactions via water molecules, which occur between specific side chains and
2700-432: A solution known as a crude lysate . The resulting mixture can be purified using ultracentrifugation , which fractionates the various cellular components into fractions containing soluble proteins; membrane lipids and proteins; cellular organelles , and nucleic acids . Precipitation by a method known as salting out can concentrate the proteins from this lysate. Various types of chromatography are then used to isolate
2808-451: A specific 3D structure that determines its activity. A linear chain of amino acid residues is called a polypeptide . A protein contains at least one long polypeptide. Short polypeptides, containing less than 20–30 residues, are rarely considered to be proteins and are commonly called peptides . The individual amino acid residues are bonded together by peptide bonds and adjacent amino acid residues. The sequence of amino acid residues in
2916-442: A variety of species contained the homeobox. Subsequent phylogenetic studies detailing the evolutionary relationship between homeobox-containing genes showed that these genes are present in all bilaterian animals. The characteristic homeodomain protein fold consists of a 60- amino acid long domain composed of three alpha helixes. The following shows the consensus homeodomain (~60 amino acid chain): Helix 2 and helix 3 form
3024-441: A variety of techniques such as ultracentrifugation , precipitation , electrophoresis , and chromatography ; the advent of genetic engineering has made possible a number of methods to facilitate purification. To perform in vitro analysis, a protein must be purified away from other cellular components. This process usually begins with cell lysis , in which a cell's membrane is disrupted and its internal contents released into
3132-432: A vast array of functions within organisms, including catalysing metabolic reactions , DNA replication , responding to stimuli , providing structure to cells and organisms , and transporting molecules from one location to another. Proteins differ from one another primarily in their sequence of amino acids, which is dictated by the nucleotide sequence of their genes , and which usually results in protein folding into
3240-538: Is a DNA sequence , around 180 base pairs long, that regulates large-scale anatomical features in the early stages of embryonic development. Mutations in a homeobox may change large-scale anatomical features of the full-grown organism. Homeoboxes are found within genes that are involved in the regulation of patterns of anatomical development ( morphogenesis ) in animals , fungi , plants , and numerous single cell eukaryotes . Homeobox genes encode homeodomain protein products that are transcription factors sharing
3348-608: Is an important regulator of plasma cell differentiation. During B cell development, a B cell can either differentiate into a short-lived plasma cell or into a germinal center B cell after receiving proper activation and co-stimulation. BLIMP-1 acts as a master gene regulating the transcriptional network that regulates B cell terminal differentiation. Except for naïve and memory B cells , all antibody secreting cells express BLIMP-1 regardless of their location and differentiation history. BLIMP-1 directly initiates unfolded protein response (UPR) by activating Ire1, Xbp1 , and Arf6 , allowing
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3456-409: Is attached to one terminus of the protein. As a result, when the lysate is passed over a chromatography column containing nickel , the histidine residues ligate the nickel and attach to the column while the untagged components of the lysate pass unimpeded. A number of different tags have been developed to help researchers purify specific proteins from complex mixtures. Homeobox A homeobox
3564-422: Is considered a 'master regulator' of hematopoietic stem cells , and plays a critical role in the development of plasma B cells , T cells , dendritic cells (DCs) , macrophages , and osteoclasts . Pattern Recognition Receptors (PRRs) can activate BLIMP-1, both as a direct target and through downstream activation. BLIMP-1 is a transcription factor that triggers expression of many downstream signaling cascades. As
3672-628: Is found in hard or filamentous structures such as hair , nails , feathers , hooves , and some animal shells . Some globular proteins can also play structural functions, for example, actin and tubulin are globular and soluble as monomers, but polymerize to form long, stiff fibers that make up the cytoskeleton , which allows the cell to maintain its shape and size. Other proteins that serve structural functions are motor proteins such as myosin , kinesin , and dynein , which are capable of generating mechanical forces. These proteins are crucial for cellular motility of single celled organisms and
3780-469: Is higher in prokaryotes than eukaryotes and can reach up to 20 amino acids per second. The process of synthesizing a protein from an mRNA template is known as translation . The mRNA is loaded onto the ribosome and is read three nucleotides at a time by matching each codon to its base pairing anticodon located on a transfer RNA molecule, which carries the amino acid corresponding to the codon it recognizes. The enzyme aminoacyl tRNA synthetase "charges"
3888-531: Is highly complex and involves reciprocal interactions, mostly inhibitory. Drosophila is known to use the polycomb and trithorax complexes to maintain the expression of Hox genes after the down-regulation of the pair-rule and gap genes that occurs during larval development. Polycomb-group proteins can silence the Hox genes by modulation of chromatin structure. Mutations to homeobox genes can produce easily visible phenotypic changes in body segment identity, such as
3996-407: Is important in dampening autoimmunity, as well as antiviral and antitumor responses. BLIMP-1 regulates T cell activation through a negative feedback loop: T cell activation leads to IL-2 production, IL-2 leads to PRDM1 transcription, and BLIMP-1 feeds back to repress IL-2 gene transcription. Multiple studies have reported high expression of BLIMP-1 in exhausted T cells . T cell exhaustion is usually
4104-461: Is inefficient for polypeptides longer than about 300 amino acids, and the synthesized proteins may not readily assume their native tertiary structure . Most chemical synthesis methods proceed from C-terminus to N-terminus, opposite the biological reaction. Most proteins fold into unique 3D structures. The shape into which a protein naturally folds is known as its native conformation . Although many proteins can fold unassisted, simply through
4212-404: Is often enormous—as much as 10 -fold increase in rate over the uncatalysed reaction in the case of orotate decarboxylase (78 million years without the enzyme, 18 milliseconds with the enzyme). The molecules bound and acted upon by enzymes are called substrates . Although enzymes can consist of hundreds of amino acids, it is usually only a small fraction of the residues that come in contact with
4320-486: Is the code for methionine . Because DNA contains four nucleotides, the total number of possible codons is 64; hence, there is some redundancy in the genetic code, with some amino acids specified by more than one codon. Genes encoded in DNA are first transcribed into pre- messenger RNA (mRNA) by proteins such as RNA polymerase . Most organisms then process the pre-mRNA (also known as a primary transcript ) using various forms of post-transcriptional modification to form
4428-776: Is the way in which individual with single nucleotide polymorphisms (SNP) near BLIMP-1 (specifically, rs548234 in Han Chinese, and rs6568431 in European) are predisposed to Systemic Lupus Erythematosus (SLE). Osteoclasts are multinucleated cells that break down and resorb bone tissues. Together with osteoblasts , which form new bones, osteoclast helps maintain and repair bone in vertebrates. BLIMP-1 directly and indirectly represses anti-osteoclastogenesis genes such as Bcl6 , IRF8 , and MafB , helping monocytes differentiate into osteoclasts. In mice, insufficient expression of BLIMP-1 in osteoclast progenitors would lead to abnormal development of
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4536-454: The Cnidaria since before the earliest true Bilatera , making these genes pre- Paleozoic . It is accepted that the three major animal ANTP-class clusters, Hox, ParaHox, and NK (MetaHox), are the result of segmental duplications. A first duplication created MetaHox and ProtoHox, the latter of which later duplicated into Hox and ParaHox. The clusters themselves were created by tandem duplications of
4644-486: The amino acid leucine for which he found a (nearly correct) molecular weight of 131 Da . Early nutritional scientists such as the German Carl von Voit believed that protein was the most important nutrient for maintaining the structure of the body, because it was generally believed that "flesh makes flesh." Around 1862, Karl Heinrich Ritthausen isolated the amino acid glutamic acid . Thomas Burr Osborne compiled
4752-583: The limb axis. Specific members of the Hox family have been implicated in vascular remodeling, angiogenesis , and disease by orchestrating changes in matrix degradation, integrins, and components of the ECM. HoxA5 is implicated in atherosclerosis. HoxD3 and HoxB3 are proinvasive, angiogenic genes that upregulate b3 and a5 integrins and Efna1 in ECs, respectively. HoxA3 induces endothelial cell (EC) migration by upregulating MMP14 and uPAR. Conversely, HoxD10 and HoxA5 have
4860-644: The muscle sarcomere , with a molecular mass of almost 3,000 kDa and a total length of almost 27,000 amino acids. Short proteins can also be synthesized chemically by a family of methods known as peptide synthesis , which rely on organic synthesis techniques such as chemical ligation to produce peptides in high yield. Chemical synthesis allows for the introduction of non-natural amino acids into polypeptide chains, such as attachment of fluorescent probes to amino acid side chains. These methods are useful in laboratory biochemistry and cell biology , though generally not for commercial applications. Chemical synthesis
4968-791: The plasma B cells to produce vast amounts of antibody. BLIMP-1 expression is carefully controlled: the expression of BLIMP-1 is low or undetectable in primary B cells, and only upregulated in plasmablasts and plasma cells. BLIMP-1 is a direct transcriptional target of IRF-4, which is also necessary for B-cell differentiation. The premature expression of BLIMP-1 in primary B cells results in cell death, so only cells that are ready to initiate transcription driven by BLIMP-1 are able to survive and differentiate. However, without BLIMP-1, proliferating B cells are unable to differentiate to plasma cells, resulting in severe reduction in production of all isotypes of immunoglobulin. BLIMP-1 promotes naive T-cells to differentiate into T-helper (Th) 2 lineage, while repressing
5076-502: The promoter region of a specific target gene. Homeodomain proteins function as transcription factors due to the DNA binding properties of the conserved HTH motif. Homeodomain proteins are considered to be master control genes, meaning that a single protein can regulate expression of many target genes. Homeodomain proteins direct the formation of the body axes and body structures during early embryonic development . Many homeodomain proteins induce cellular differentiation by initiating
5184-645: The sperm of many multicellular organisms which reproduce sexually . They also generate the forces exerted by contracting muscles and play essential roles in intracellular transport. A key question in molecular biology is how proteins evolve, i.e. how can mutations (or rather changes in amino acid sequence) lead to new structures and functions? Most amino acids in a protein can be changed without disrupting activity or function, as can be seen from numerous homologous proteins across species (as collected in specialized databases for protein families , e.g. PFAM ). In order to prevent dramatic consequences of mutations,
5292-622: The "homeobox". The existence of additional Drosophila genes containing the antennapedia homeobox sequence was independently reported by Ernst Hafen, Michael Levine , William McGinnis , and Walter Jakob Gehring of the University of Basel in Switzerland and Matthew P. Scott and Amy Weiner of Indiana University in Bloomington in 1984. Isolation of homologous genes by Edward de Robertis and William McGinnis revealed that numerous genes from
5400-493: The 1700s by Antoine Fourcroy and others, who often collectively called them " albumins ", or "albuminous materials" ( Eiweisskörper , in German). Gluten , for example, was first separated from wheat in published research around 1747, and later determined to exist in many plants. In 1789, Antoine Fourcroy recognized three distinct varieties of animal proteins: albumin , fibrin , and gelatin . Vegetable (plant) proteins studied in
5508-562: The 1950s, the Armour Hot Dog Company purified 1 kg of pure bovine pancreatic ribonuclease A and made it freely available to scientists; this gesture helped ribonuclease A become a major target for biochemical study for the following decades. The understanding of proteins as polypeptides , or chains of amino acids, came through the work of Franz Hofmeister and Hermann Emil Fischer in 1902. The central role of proteins as enzymes in living organisms that catalyzed reactions
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#17330861178715616-498: The 20,000 or so proteins encoded by the human genome, only 6,000 are detected in lymphoblastoid cells. Proteins are assembled from amino acids using information encoded in genes. Each protein has its own unique amino acid sequence that is specified by the nucleotide sequence of the gene encoding this protein. The genetic code is a set of three-nucleotide sets called codons and each three-nucleotide combination designates an amino acid, for example AUG ( adenine – uracil – guanine )
5724-547: The Antennapedia and Bithorax mutant phenotypes in Drosophila . Duplication of homeobox genes can produce new body segments, and such duplications are likely to have been important in the evolution of segmented animals. Phylogenetic analysis of homeobox gene sequences and homeodomain protein structures suggests that the last common ancestor of plants, fungi, and animals had at least two homeobox genes. Molecular evidence shows that some limited number of Hox genes have existed in
5832-479: The BLIMP-1 protein in B lymphocytes , T lymphocytes , NK cells and other immune system cells leads to an immune response through proliferation and differentiation of antibody secreting plasma cells . In a monocytic cell line, over-expression of BLIMP-1 can lead to differentiation into mature macrophages . BLIMP-1 also plays a role in osteoclastogenesis as well as in the modulation of dendritic cells . Other cells of
5940-538: The C-terminal recognition helix aligning in the DNA's major groove and the unstructured peptide "tail" at the N-terminus aligning in the minor groove. The recognition helix and the inter-helix loops are rich in arginine and lysine residues, which form hydrogen bonds to the DNA backbone. Conserved hydrophobic residues in the center of the recognition helix aid in stabilizing the helix packing. Homeodomain proteins show
6048-516: The EC number system provides a functional classification scheme. Similarly, the gene ontology classifies both genes and proteins by their biological and biochemical function, but also by their intracellular location. Sequence similarity is used to classify proteins both in terms of evolutionary and functional similarity. This may use either whole proteins or protein domains , especially in multi-domain proteins . Protein domains allow protein classification by
6156-679: The IFN-β promoter due to its sequence similarity with IRF1 and IRF2. However, BLIMP-1 cools down and activates immune responses in a highly contextual manner. BLIMP-1 represses NFκB / TNF-R pathway repressor NLRP12 , thus indirectly activating the immune response. BLIMP-1 expression is also upregulated by danger signals from double-stranded RNA (specific to virus), lipopolysaccharides (specific to gram-negative bacteria ), unmethylated CpG DNA (abundant in bacterial genomes), and cancer inflammation via Toll-like receptor (TLR) 3 , TLR-4 , TLR-9 , and STAT signaling, respectively. The increased expression of
6264-581: The PRDM1 gene that predict an increased likelihood of developing a second cancer after radiation treatment for Hodgkin lymphoma . This article incorporates text from the United States National Library of Medicine , which is in the public domain . Protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues . Proteins perform
6372-709: The ability of many enzymes to bind and process multiple substrates . When mutations occur, the specificity of an enzyme can increase (or decrease) and thus its enzymatic activity. Thus, bacteria (or other organisms) can adapt to different food sources, including unnatural substrates such as plastic. Methods commonly used to study protein structure and function include immunohistochemistry , site-directed mutagenesis , X-ray crystallography , nuclear magnetic resonance and mass spectrometry . The activities and structures of proteins may be examined in vitro , in vivo , and in silico . In vitro studies of purified proteins in controlled environments are useful for learning how
6480-405: The addition of a single methyl group to a binding partner can sometimes suffice to nearly eliminate binding; for example, the aminoacyl tRNA synthetase specific to the amino acid valine discriminates against the very similar side chain of the amino acid isoleucine . Proteins can bind to other proteins as well as to small-molecule substrates. When proteins bind specifically to other copies of
6588-595: The alpha carbons are roughly coplanar . The other two dihedral angles in the peptide bond determine the local shape assumed by the protein backbone. The end with a free amino group is known as the N-terminus or amino terminus, whereas the end of the protein with a free carboxyl group is known as the C-terminus or carboxy terminus (the sequence of the protein is written from N-terminus to C-terminus, from left to right). The words protein , polypeptide, and peptide are
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#17330861178716696-531: The amino acid side chains in a protein that ultimately determines its three-dimensional structure and its chemical reactivity. The amino acids in a polypeptide chain are linked by peptide bonds . Once linked in the protein chain, an individual amino acid is called a residue, and the linked series of carbon, nitrogen, and oxygen atoms are known as the main chain or protein backbone. The peptide bond has two resonance forms that contribute some double-bond character and inhibit rotation around its axis, so that
6804-451: The antenna on the head of a fruit fly with legs. The "homeo-" prefix in the words "homeobox" and "homeodomain" stems from this mutational phenotype , which is observed when some of these genes are mutated in animals . The homeobox domain was first identified in a number of Drosophila homeotic and segmentation proteins, but is now known to be well-conserved in many other animals, including vertebrates . The existence of homeobox genes
6912-574: The binding of a substrate molecule to an enzyme's active site , or the physical region of the protein that participates in chemical catalysis. In solution, proteins also undergo variation in structure through thermal vibration and the collision with other molecules. Proteins can be informally divided into three main classes, which correlate with typical tertiary structures: globular proteins , fibrous proteins , and membrane proteins . Almost all globular proteins are soluble and many are enzymes. Fibrous proteins are often structural, such as collagen ,
7020-570: The body of a multicellular organism. These proteins must have a high binding affinity when their ligand is present in high concentrations, but must also release the ligand when it is present at low concentrations in the target tissues. The canonical example of a ligand-binding protein is haemoglobin , which transports oxygen from the lungs to other organs and tissues in all vertebrates and has close homologs in every biological kingdom . Lectins are sugar-binding proteins which are highly specific for their sugar moieties. Lectins typically play
7128-504: The cascades of coregulated genes required to produce individual tissues and organs . Other proteins in the family, such as NANOG are involved in maintaining pluripotency and preventing cell differentiation. Hox genes and their associated microRNAs are highly conserved developmental master regulators with tight tissue-specific, spatiotemporal control. These genes are known to be dysregulated in several cancers and are often controlled by DNA methylation. The regulation of Hox genes
7236-558: The cell is as enzymes , which catalyse chemical reactions. Enzymes are usually highly specific and accelerate only one or a few chemical reactions. Enzymes carry out most of the reactions involved in metabolism , as well as manipulating DNA in processes such as DNA replication , DNA repair , and transcription . Some enzymes act on other proteins to add or remove chemical groups in a process known as posttranslational modification. About 4,000 reactions are known to be catalysed by enzymes. The rate acceleration conferred by enzymatic catalysis
7344-436: The cell surface and an effector domain within the cell, which may have enzymatic activity or may undergo a conformational change detected by other proteins within the cell. Antibodies are protein components of an adaptive immune system whose main function is to bind antigens , or foreign substances in the body, and target them for destruction. Antibodies can be secreted into the extracellular environment or anchored in
7452-752: The cell's machinery through the process of protein turnover . A protein's lifespan is measured in terms of its half-life and covers a wide range. They can exist for minutes or years with an average lifespan of 1–2 days in mammalian cells. Abnormal or misfolded proteins are degraded more rapidly either due to being targeted for destruction or due to being unstable. Like other biological macromolecules such as polysaccharides and nucleic acids , proteins are essential parts of organisms and participate in virtually every process within cells . Many proteins are enzymes that catalyse biochemical reactions and are vital to metabolism . Proteins also have structural or mechanical functions, such as actin and myosin in muscle and
7560-450: The cell. Many ion channel proteins are specialized to select for only a particular ion; for example, potassium and sodium channels often discriminate for only one of the two ions. Structural proteins confer stiffness and rigidity to otherwise-fluid biological components. Most structural proteins are fibrous proteins ; for example, collagen and elastin are critical components of connective tissue such as cartilage , and keratin
7668-494: The characteristic migration, proliferation and consistent repression of homeobox genes that normally accompany specification of primordial germ cells. BLIMP-1 is widely expressed in stem cells of developing embryos. The genetic lineage-tracing experiments indicate that the BLIMP-1-positive cells originating from the proximal posterior epiblast cells are indeed the lineage-restricted primordial germ cell precursors. BLIMP-1
7776-621: The chemical properties of their amino acids, others require the aid of molecular chaperones to fold into their native states. Biochemists often refer to four distinct aspects of a protein's structure: Proteins are not entirely rigid molecules. In addition to these levels of structure, proteins may shift between several related structures while they perform their functions. In the context of these functional rearrangements, these tertiary or quaternary structures are usually referred to as " conformations ", and transitions between them are called conformational changes. Such changes are often induced by
7884-441: The chief actors within the cell, said to be carrying out the duties specified by the information encoded in genes. With the exception of certain types of RNA , most other biological molecules are relatively inert elements upon which proteins act. Proteins make up half the dry weight of an Escherichia coli cell, whereas other macromolecules such as DNA and RNA make up only 3% and 20%, respectively. The set of proteins expressed in
7992-490: The construction of enormously complex signaling networks. As interactions between proteins are reversible, and depend heavily on the availability of different groups of partner proteins to form aggregates that are capable to carry out discrete sets of function, study of the interactions between specific proteins is a key to understand important aspects of cellular function, and ultimately the properties that distinguish particular cell types. The best-known role of proteins in
8100-408: The derivative unit kilodalton (kDa). The average size of a protein increases from Archaea to Bacteria to Eukaryote (283, 311, 438 residues and 31, 34, 49 kDa respectively) due to a bigger number of protein domains constituting proteins in higher organisms. For instance, yeast proteins are on average 466 amino acids long and 53 kDa in mass. The largest known proteins are the titins , a component of
8208-512: The differentiation into Th1, Th17, and follicular Th. BLIMP-1 is also required for differentiation of cytotoxic T-cell . Specifically, the expression of granzyme B (a source of cytotoxicity) in Tc depends on the presence of BLIMP-1 and interleukin-2 ( IL-2 ) cytokine. BLIMP-1 is a gatekeeper of T-cell activation and plays a key role in maintaining normal T cell homeostasis . BLIMP-1 deficiency leads to high numbers of activated T helper cells and severe autoimmune diseases in laboratory mice. BLIMP-1
8316-447: The erroneous conclusion that they might be composed of a single type of (very large) molecule. The term "protein" to describe these molecules was proposed by Mulder's associate Berzelius; protein is derived from the Greek word πρώτειος ( proteios ), meaning "primary", "in the lead", or "standing in front", + -in . Mulder went on to identify the products of protein degradation such as
8424-552: The exposed bases within the major groove of the DNA. Homeodomain proteins are found in eukaryotes . Through the HTH motif, they share limited sequence similarity and structural similarity to prokaryotic transcription factors, such as lambda phage proteins that alter the expression of genes in prokaryotes . The HTH motif shows some sequence similarity but a similar structure in a wide range of DNA-binding proteins (e.g., cro and repressor proteins , homeodomain proteins, etc.). One of
8532-456: The identity of embryonic regions along the anterior-posterior axis. The first vertebrate Hox gene was isolated in Xenopus by Edward De Robertis and colleagues in 1984. The main interest in this set of genes stems from their unique behavior and arrangement in the genome. Hox genes are typically found in an organized cluster. The linear order of Hox genes within a cluster is directly correlated to
8640-424: The immune system such as human peripheral blood monocytes and granulocytes also express BLIMP-1. As a transcriptional repressor , BLIMP-1 has a critical role in the foundation of the mouse germ cell lineage, as its disruption causes a block early in the process of primordial germ cell formation. BLIMP-1-deficient mutant embryos form a tight cluster of about 20 primordial germ cell-like cells, which fail to show
8748-500: The initial letters of the names of three proteins where the characteristic domain was first identified) encode two 60 amino acid cysteine and histidine-rich LIM domains and a homeodomain. The LIM domains function in protein-protein interactions and can bind zinc molecules. LIM domain proteins are found in both the cytosol and the nucleus. They function in cytoskeletal remodeling, at focal adhesion sites, as scaffolds for protein complexes, and as transcription factors. Most Pax genes contain
8856-525: The late 1700s and early 1800s included gluten , plant albumin , gliadin , and legumin . Proteins were first described by the Dutch chemist Gerardus Johannes Mulder and named by the Swedish chemist Jöns Jacob Berzelius in 1838. Mulder carried out elemental analysis of common proteins and found that nearly all proteins had the same empirical formula , C 400 H 620 N 100 O 120 P 1 S 1 . He came to
8964-478: The major component of connective tissue, or keratin , the protein component of hair and nails. Membrane proteins often serve as receptors or provide channels for polar or charged molecules to pass through the cell membrane . A special case of intramolecular hydrogen bonds within proteins, poorly shielded from water attack and hence promoting their own dehydration , are called dehydrons . Many proteins are composed of several protein domains , i.e. segments of
9072-443: The mature mRNA, which is then used as a template for protein synthesis by the ribosome . In prokaryotes the mRNA may either be used as soon as it is produced, or be bound by a ribosome after having moved away from the nucleoid . In contrast, eukaryotes make mRNA in the cell nucleus and then translocate it across the nuclear membrane into the cytoplasm , where protein synthesis then takes place. The rate of protein synthesis
9180-405: The membranes of specialized B cells known as plasma cells . Whereas enzymes are limited in their binding affinity for their substrates by the necessity of conducting their reaction, antibodies have no such constraints. An antibody's binding affinity to its target is extraordinarily high. Many ligand transport proteins bind particular small biomolecules and transport them to other locations in
9288-444: The migration of T cells out of the spleen and lymph nodes into peripheral tissues. However, BLIMP-1 does not promote the production of long-lived effector memory cells. BLIMP-1 allows the production of some longer lived effector memory cells but its absence allows for the generation of long term central memory cells, which are thought to have a higher potential of proliferation on secondary challenge. BLIMP-1 has been shown in vitro as
9396-496: The nobel prize in 1972, solidified the thermodynamic hypothesis of protein folding, according to which the folded form of a protein represents its free energy minimum. With the development of X-ray crystallography , it became possible to determine protein structures as well as their sequences. The first protein structures to be solved were hemoglobin by Max Perutz and myoglobin by John Kendrew , in 1958. The use of computers and increasing computing power also supported
9504-710: The opposite effect of suppressing EC migration and angiogenesis, and stabilizing adherens junctions by upregulating TIMP1/downregulating uPAR and MMP14, and by upregulating Tsp2/downregulating VEGFR2, Efna1, Hif1alpha and COX-2, respectively. HoxA5 also upregulates the tumor suppressor p53 and Akt1 by downregulation of PTEN. Suppression of HoxA5 has been shown to attenuate hemangioma growth. HoxA5 has far-reaching effects on gene expression, causing ~300 genes to become upregulated upon its induction in breast cancer cell lines. HoxA5 protein transduction domain overexpression prevents inflammation shown by inhibition of TNFalpha-inducible monocyte binding to HUVECs. LIM genes (named after
9612-751: The optic vesicle and subsequent eye structures. Proteins containing a POU region consist of a homeodomain and a separate, structurally homologous POU domain that contains two helix-turn-helix motifs and also binds DNA. The two domains are linked by a flexible loop that is long enough to stretch around the DNA helix, allowing the two domains to bind on opposite sides of the target DNA, collectively covering an eight-base segment with consensus sequence 5'-ATGCAAAT-3'. The individual domains of POU proteins bind DNA only weakly, but have strong sequence-specific affinity when linked. The POU domain itself has significant structural similarity with repressors expressed in bacteriophages , particularly lambda phage . As in animals,
9720-500: The order of 50,000 to 1 million. By contrast, eukaryotic cells are larger and thus contain much more protein. For instance, yeast cells have been estimated to contain about 50 million proteins and human cells on the order of 1 to 3 billion. The concentration of individual protein copies ranges from a few molecules per cell up to 20 million. Not all genes coding proteins are expressed in most cells and their number depends on, for example, cell type and external stimuli. For instance, of
9828-406: The order they are expressed in both time and space during development. This phenomenon is called colinearity. Mutations in these homeotic genes cause displacement of body segments during embryonic development. This is called ectopia . For example, when one gene is lost the segment develops into a more anterior one, while a mutation that leads to a gain of function causes a segment to develop into
9936-440: The physical and chemical properties, folding, stability, activity, and ultimately, the function of the proteins. Some proteins have non-peptide groups attached, which can be called prosthetic groups or cofactors . Proteins can also work together to achieve a particular function, and they often associate to form stable protein complexes . Once formed, proteins only exist for a certain period and are then degraded and recycled by
10044-516: The plant homeobox genes code for the typical 60 amino acid long DNA-binding homeodomain or in case of the TALE (three amino acid loop extension) homeobox genes for an atypical homeodomain consisting of 63 amino acids. According to their conserved intron–exon structure and to unique codomain architectures they have been grouped into 14 distinct classes: HD-ZIP I to IV, BEL, KNOX, PLINC, WOX, PHD, DDT, NDX, LD, SAWADEE and PINTOX. Conservation of codomains suggests
10152-466: The principal differences between HTH motifs in these different proteins arises from the stereochemical requirement for glycine in the turn which is needed to avoid steric interference of the beta-carbon with the main chain: for cro and repressor proteins the glycine appears to be mandatory, whereas for many of the homeotic and other DNA-binding proteins the requirement is relaxed. Homeodomains can bind both specifically and nonspecifically to B-DNA with
10260-424: The process of cell signaling and signal transduction . Some proteins, such as insulin , are extracellular proteins that transmit a signal from the cell in which they were synthesized to other cells in distant tissues . Others are membrane proteins that act as receptors whose main function is to bind a signaling molecule and induce a biochemical response in the cell. Many receptors have a binding site exposed on
10368-534: The protein or proteins of interest based on properties such as molecular weight, net charge and binding affinity. The level of purification can be monitored using various types of gel electrophoresis if the desired protein's molecular weight and isoelectric point are known, by spectroscopy if the protein has distinguishable spectroscopic features, or by enzyme assays if the protein has enzymatic activity. Additionally, proteins can be isolated according to their charge using electrofocusing . For natural proteins,
10476-427: The proteins in the cytoskeleton , which form a system of scaffolding that maintains cell shape. Other proteins are important in cell signaling, immune responses , cell adhesion , and the cell cycle . In animals, proteins are needed in the diet to provide the essential amino acids that cannot be synthesized . Digestion breaks the proteins down for metabolic use. Proteins have been studied and recognized since
10584-582: The same molecule, they can oligomerize to form fibrils; this process occurs often in structural proteins that consist of globular monomers that self-associate to form rigid fibers. Protein–protein interactions also regulate enzymatic activity, control progression through the cell cycle , and allow the assembly of large protein complexes that carry out many closely related reactions with a common biological function. Proteins can also bind to, or even be integrated into, cell membranes. The ability of binding partners to induce conformational changes in proteins allows
10692-573: The sample, allowing scientists to obtain more information and analyze larger structures. Computational protein structure prediction of small protein structural domains has also helped researchers to approach atomic-level resolution of protein structures. As of April 2024 , the Protein Data Bank contains 181,018 X-ray, 19,809 EM and 12,697 NMR protein structures. Proteins are primarily classified by sequence and structure, although other classifications are commonly used. Especially for enzymes
10800-430: The sequencing of complex proteins. In 1999, Roger Kornberg succeeded in sequencing the highly complex structure of RNA polymerase using high intensity X-rays from synchrotrons . Since then, cryo-electron microscopy (cryo-EM) of large macromolecular assemblies has been developed. Cryo-EM uses protein samples that are frozen rather than crystals, and beams of electrons rather than X-rays. It causes less damage to
10908-498: The skeleton. SNPs near the PRDM1 gene have been identified in genome-wide association studies (GWAS) to be linked to lupus (SLE) and rheumatoid arthritis (RA) . BLIMP-1 represses the expression of the proinflammatory cytokine Interleukin-6 (IL-6), and cathepsin S (CTSS), which promotes antigen processing and presentation. BLIMP-1 deficiency and IL-6 overexpression were linked to inflammatory bowel disease (IBD) and SLE. Another GWAS has identified two genetic variations near
11016-405: The substrate, and an even smaller fraction—three to four residues on average—that are directly involved in catalysis. The region of the enzyme that binds the substrate and contains the catalytic residues is known as the active site . Dirigent proteins are members of a class of proteins that dictate the stereochemistry of a compound synthesized by other enzymes. Many proteins are involved in
11124-706: The surrounding amino acids may determine the exact binding specificity). Many such motifs has been collected in the Eukaryotic Linear Motif (ELM) database. Topology of a protein describes the entanglement of the backbone and the arrangement of contacts within the folded chain. Two theoretical frameworks of knot theory and Circuit topology have been applied to characterise protein topology. Being able to describe protein topology opens up new pathways for protein engineering and pharmaceutical development, and adds to our understanding of protein misfolding diseases such as neuromuscular disorders and cancer. Proteins are
11232-400: The tRNA molecules with the correct amino acids. The growing polypeptide is often termed the nascent chain . Proteins are always biosynthesized from N-terminus to C-terminus . The size of a synthesized protein can be measured by the number of amino acids it contains and by its total molecular mass , which is normally reported in units of daltons (synonymous with atomic mass units ), or
11340-472: The tertiary structure of the protein, which defines the binding site pocket, and by the chemical properties of the surrounding amino acids' side chains. Protein binding can be extraordinarily tight and specific; for example, the ribonuclease inhibitor protein binds to human angiogenin with a sub-femtomolar dissociation constant (<10 M) but does not bind at all to its amphibian homolog onconase (> 1 M). Extremely minor chemical changes such as
11448-466: Was insulin , by Frederick Sanger , in 1949. Sanger correctly determined the amino acid sequence of insulin, thus conclusively demonstrating that proteins consisted of linear polymers of amino acids rather than branched chains, colloids , or cyclols . He won the Nobel Prize for this achievement in 1958. Christian Anfinsen 's studies of the oxidative folding process of ribonuclease A, for which he won
11556-463: Was first discovered in Drosophila by isolating the gene responsible for a homeotic transformation where legs grow from the head instead of the expected antennae. Walter Gehring identified a gene called antennapedia that caused this homeotic phenotype. Analysis of antennapedia revealed that this gene contained a 180 base pair sequence that encoded a DNA binding domain, which William McGinnis termed
11664-581: Was not fully appreciated until 1926, when James B. Sumner showed that the enzyme urease was in fact a protein. Linus Pauling is credited with the successful prediction of regular protein secondary structures based on hydrogen bonding , an idea first put forth by William Astbury in 1933. Later work by Walter Kauzmann on denaturation , based partly on previous studies by Kaj Linderstrøm-Lang , contributed an understanding of protein folding and structure mediated by hydrophobic interactions . The first protein to have its amino acid chain sequenced
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