98-399: 3A7Q 7804 16975 ENSG00000157193 ENSMUSG00000028613 Q14114 Q924X6 NM_001018054 NM_004631 NM_017522 NM_033300 NM_001369054 NP_001018064 NP_004622 NP_059992 NP_150643 NP_444303 Low-density lipoprotein receptor-related protein 8 ( LRP8 ), also known as apolipoprotein E receptor 2 ( ApoER2 ), is a protein that in humans
196-516: 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
294-470: 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.
392-541: A phosphoprotein that binds nonreceptor tyrosine kinases and that has been implicated in neuronal development in flies. Sheldon et al. (1997) found that the yotari phenotype also results from a mutation in the Dab1 gene. Using in situ hybridization to embryonic day-13.5 mouse brain tissue, they demonstrated that Dab1 is expressed in neuronal populations exposed to reelin. The authors concluded that reelin and Dab1 function as signaling molecules that regulate cell positioning in
490-552: 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,
588-403: 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
686-834: 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
784-771: A key regulator of Reelin signaling. Reelin is a large glycoprotein secreted by neurons of the developing brain, particularly Cajal-Retzius cells . DAB1 functions downstream of Reln in a signaling pathway that controls cell positioning in the developing brain and during adult neurogenesis . It docks to the intracellular part of the Reelin very low density lipoprotein receptor ( VLDLR ) and apoE receptor type 2 ( ApoER2 ) and becomes tyrosine-phosphorylated following binding of Reelin to cortical neurons. In mice, mutations of Dab1 and Reelin generate identical phenotypes . In humans, Reelin mutations are associated with brain malformations and mental retardation . In mice, Dab1 mutation results in
882-478: 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
980-443: A much greater impairment of LTP than knocking out VLDLR. Apolipoprotein E (ApoE) plays an important role in phospholipid and cholesterol homeostasis. After binding ApoER2, ApoE is taken up into the cell and may remain in the intracellular space, be shipped to the cell surface, or be degraded. ApoE binding leads to the cleavage of ApoER2 into secreted proteins by the actions of the plasma membrane protein gamma secretase . ApoE may be
1078-410: 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
SECTION 10
#17328767383801176-580: A phenotype identical to that of reeler. Ware et al. (1997) determined that the scrambler phenotype arises from mutations in Dab1, a mouse gene related to the Drosophila gene 'disabled' (dab). Disabled-1 (Dab1) is an adaptor protein that is essential for the intracellular transduction of Reelin signaling, which regulates the migration and differentiation of postmitotic neurons during brain development in vertebrates. Dab1 function depends on its tyrosine phosphorylation by Src family kinases, especially Fyn. Dab encodes
1274-500: 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
1372-411: 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
1470-539: 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
1568-486: 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
1666-485: A role in regulating synaptic plasticity. VLDLR also acts as a receptor coupled to ApoER2 as it does during development, but its role is not well understood. ApoER2 plays a more important role in this process, most likely due to its ability to bind the PSD-95 adapter protein through the 59 amino acid insert on its cytoplasmic tail. Studies with mice have shown that knocking out ApoER2 or just the alternatively spliced exon 19 causes
1764-406: 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 "),
1862-432: 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
1960-441: 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
2058-557: Is a proline-rich 59 amino acid insert encoded by the alternatively spliced exon 19. This insert allows for protein interactions that are unable to occur with other LDL receptors . It binds the PSD-95 adapter protein, cross-linking ApoER2 and the NMDA receptors during the process of long-term potentiation , and is also bound specifically by JIP-2 , an important interaction in the JNK signalling pathway. It
SECTION 20
#17328767383802156-448: Is also speculated that this insert may diminish the function of ApoER2 in lipoprotein endocytosis by somehow disrupting the NPXY motif. ApoER2 plays a critical role as a receptor in the reelin signalling pathway, which is important for brain development and postnatal function of the brain. This pathway specifically affects cortical migration and long-term potentiation. In development, reelin
2254-426: Is associated with certain neurological diseases. ApoER2 is a protein made up of 870 amino acids. It is separated into a ligand binding domain of eight ligand binding regions, an EGF-like domain containing three cysteine -rich repeats, an O-linked glycosylation domain of 89 amino acids, a transmembrane domain of 24 amino acids, and a cytoplasmic domain of 115 amino acids, including an NPXY motif. Each letter in
2352-699: 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. DAB1 1NTV , 1NU2 , 1OQN 1600 13131 ENSG00000173406 ENSMUSG00000028519 O75553 P97318 NM_021080 NM_001369049 NP_001352721 NP_001352722 NP_001352723 NP_001352724 NP_001366390 NP_001366391 NP_001355978 The Disabled-1 ( Dab1 ) gene encodes
2450-775: Is controlled by proteolytic inhibitors such as alpha-2-macroglobulin. Studies have shown that a high presence of alpha-2-macroglobulin is present in the neuritic plaques in many Alzheimer patients. Isolation of cDNA encoding proteins associated with Aβ was used to discover alpha-2-macroglobulin. These discoveries may link alpha-2-macroglobulin and its receptors, one of them being ApoER2, to Alzheimer's disease. ApoER2 interaction with reelin and ApoE has implications with Alzheimer's disease. Binding of reelin to ApoER2 leads to cascade of signals that modulate NMDA receptor functions. ApoE competes with reelin in binding to ApoER2 resulting in weakened reelin signaling. Reduced reelin signaling leads to impaired plasticity in neurons and increases in
2548-562: Is dictated by the nucleotide sequence of their genes , and which usually results in protein folding into 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
2646-595: Is encoded by the LRP8 gene . ApoER2 is a cell surface receptor that is part of the low-density lipoprotein receptor family . These receptors function in signal transduction and endocytosis of specific ligands. Through interactions with one of its ligands, reelin , ApoER2 plays an important role in embryonic neuronal migration and postnatal long-term potentiation . Another LDL family receptor, VLDLR , also interacts with reelin, and together these two receptors influence brain development and function. Decreased expression of ApoER2
2744-495: Is essential in development of memory and spatial learning. Studies with mice have shown less expression of ApoER2 leads to impaired spatial learning, fear conditioned learning, and a mild disruption to the hippocampus. In the hippocampus, ApoER2 is complexed with NMDA receptors through the PSD-95 adapter protein. When reelin binds ApoER2, it initiates tyrosine phosphorylation of NMDA receptors. This occurs through Dab-1 activation of Src family kinases , which have been shown to play
2842-628: 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
2940-469: 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"
3038-461: 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
Low-density lipoprotein receptor-related protein 8 - Misplaced Pages Continue
3136-466: Is involved with cell-to-cell communication and migration of neurons, and causes the activation of Dab1. F-spondin is a secreted protein that also binds ApoER2 and leads to phosphorylation of Dab1. Alzheimer's disease is the most common form of dementia, and studies have shown that manipulation of pathways involving LRP8/ApoER2 can lead to the disease. Certain alleles , such as apoe , app , ps1 and ps2 , may lead to being genetically predisposed to
3234-406: Is necessary in the testes for proper spermatozoa development. Mice that have had their ApoER2 or Selenoprotein P expression knocked out show impaired spermatozoa development and decreased fertility. In the brain, deficiencies in selenium and selenium uptake mechanisms result in brain damage. Thrombospondin is a protein found in the extracellular matrix that competes with reelin to bind ApoER2. It
3332-404: 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
3430-534: Is one of the hallmarks of Alzheimer's disease. The role of ApoER2 in Alzheimer's disease is relevant, yet incompletely understood. New evidence suggests ApoER2 plays a major role in the regulation of amyloid-β formation in the brain. The amyloid-β peptide is derived from the cleavage of APP by gamma secretase. ApoER2 works to reduce APP trafficking by altering break down. This interaction decreases APP endocytosis leading to an increase in amyloid-β production. In addition,
3528-409: Is secreted by Cajal-Retzius cells . Reelin acts as an extracellular ligand binding to ApoER2 and VLDLR on migrating neurons. A specific lysine residue on reelin binds to the first repeat on the ligand binding domain of ApoER2. This interaction with the two receptors activates intracellular processes that begin with the phosphorylation of Dab1, a tyrosine kinase phosphorylated protein which is encoded by
3626-404: Is secreted in the cortex and hippocampus by gamma-aminobutyric acid-ergic interneurons. Through binding of ApoER2 in the hippocampus, it plays a role in the NMDA receptor activation that is required for long-term potentiation, a mechanism by which two neurons gain a stronger, longer-lasting transmission due to simultaneous firing. The increased synaptic plasticity associated with this process
3724-532: 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
3822-415: The scrambler mouse phenotype. With a genomic length of 1.1 Mbp for a coding region of 5.5 kb, DAB1 provides a rare example of genomic complexity, which will impede the identification of human mutations. Cortical neurons form in specialized proliferative regions deep in the brain and migrate past previously formed neurons to reach their proper layer. The laminar organization of multiple neuronal types in
3920-509: The DAB1 gene. This protein associates with the NPXY motifs on the intracellular tails of ApoER2 and VLDLR. Upon reelin binding, Dab1 is phosphorylated by two tyrosine kinases , Fyn and Src . The phosphorylated Dab1 then causes further activation of these two kinases and others, including a phosphatidylinositol-3-kinase (PI3K). PI3K activation leads to inhibitory phosphorylation of the tau kinase glycogen synthase kinase 3 beta ( GSK3B ), which alters
4018-486: 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
Low-density lipoprotein receptor-related protein 8 - Misplaced Pages Continue
4116-429: The cerebral cortex is required for normal cognitive function . The mouse ' reeler ' mutation causes abnormal patterns of cortical neuronal migration as well as additional defects in cerebellar development and neuronal positioning in other brain regions. Reelin (RELN; 600514), the reeler gene product, is an extracellular protein secreted by pioneer neurons . The mouse 'scrambler' and ' yotari ' recessive mutations exhibit
4214-644: 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
4312-605: The phosphorylation of tau protein, which is a microtubule stabilizing protein that is abundant in the Central Nervous System (CNS), producing neurofibrillary tangles which are implicated in Alzheimer's disease. Antiphospholipid syndrome is an autoimmune disease characterized by thrombosis and complications during pregnancy, often leading to fetal death . It is caused by the presence of antibodies against anionic phospholipids and β2-glycoprotein I (β2GPI). The anti-β2GPI antibodies are most prevalent in causing
4410-455: The reeler gene results in aberrant migration as well as outside-in layering, in which younger neurons are unable to travel past the older ones. Such abnormal layering is also seen in VLDLR − apoER2 − and dab1 - mutants, indicating the importance of this entire pathway in cortical migration of the developing embryo. There is some confusion as to the exact function of the reelin-signalling pathway in
4508-645: 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,
4606-408: The symptoms of the disease. When bound by an antibody, β2GPI begins to interact with monocytes , endothelial cells , and platelets . ApoER2 is thought to play a key role in the process of platelet binding. β2GPI has the proper binding site for interaction with ApoER2 and other LDL family receptors, and it is speculated that the antibody/β2GPI complexes interact with ApoER2 on platelets. This causes
4704-493: 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
4802-562: 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
4900-498: 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 )
4998-516: 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
SECTION 50
#17328767383805096-601: The JNK-signaling pathway and interact with exon 19 of ApoER2. For JIP2, interaction with exon 19 of ApoER2 is through the PID domain. This interaction has led researchers to believe that ApoER2 is involved in many interactions at the surface of cells. Selenoprotein P transports the trace element selenium from the liver to the testes and brain, and binds to ApoER2 in these areas. ApoER2 functions to internalize this complex to maintain normal levels of selenium in these cells. Selenium
5194-490: The NPXY motif represents a certain amino acid where N is arginine , P is proline , X is any amino acid, and Y is tyrosine . All LDL receptor family proteins contain a cytoplasmic tail with at least one NPXY motif. This motif is important for binding intracellular adapter proteins and endocytosis . ApoER2 is distinct from most other members of the LDL family of receptors due to a unique insert on its cytoplasmic tail. In ApoER2, there
5292-709: 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
5390-492: The activity of tau protein, a protein involved in stabilizing microtubules. This transduction is combined with the activation of other pathways that influence the cytoskeletal rearrangement necessary for proper cortical cell migration. The result of proper neuronal migration through the cortical plate (CP) is an inside-out arrangement of neurons, where the younger neurons migrate past the older neurons to their proper locations. Studies in reeler mutant mice show that knocking out
5488-405: 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
5586-595: 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
5684-531: 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
5782-574: 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 ,
5880-570: 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
5978-558: 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
SECTION 60
#17328767383806076-436: 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
6174-752: 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
6272-450: 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
6370-621: 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
6468-441: 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
6566-490: 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
6664-408: 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
6762-690: The developing brain. Howell et al. (1997) showed that targeted disruption of the Dab1 gene disturbed neuronal layering in the cerebral cortex , hippocampus , and cerebellum , causing a reeler-like phenotype. Layering of neurons in the cerebral cortex and cerebellum requires RELN and DAB1. By targeted disruption experiments in mice, Trommsdorff et al. (1999) showed that 2 cell surface receptors, very low density lipoprotein receptor (VLDLR; 192977) and apolipoprotein E receptor-2 ( ApoER2 ; 602600), are also required. Both receptors bound Dab1 on their cytoplasmic tails and were expressed in cortical and cerebellar layers adjacent to layers expressing Reln. Dab1 expression
6860-583: The disease. A decrease in LRP8 expression is observed in patients with Alzheimer's disease. An example of a decrease in expression of LRP8 is when gamma secretase cleaves LRP8 as well as the ligand amyloid precursor protein (APP). The degradation products control transcription factors, which lead to the expression of a tau protein . The cascade dysfunction caused by the altered gene expression may be implicated with Alzheimer's disease. The presence of amyloid beta (Aβ) protein deposits in neuronal extracellular space
6958-447: 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
7056-413: The expression of ApoER2 within intracellular compartments leads to increased gamma secretase activity, a protease which works to cleave APP into Aβ. ApoER2 splice variants can act as a receptor for alpha-2-macroglobulin which can have a role in clearance of alpha-2-macroglobulin/proteinase complex. Proteases may play a role in synaptic plasticity balancing proteolytic activity and inhibition, which
7154-399: The extracellular RELN signal to intracellular signaling processes initiated by DAB1. In the reeler mouse, the telencephalic neurons (which are misplaced following migration) express approximately 10-fold more DAB1 than their wildtype counterpart. Such an increase in the expression of a protein that virtually functions as a receptor is expected to occur when the specific signal for the receptor
7252-639: The key ferroptosis regulator and selenoprotein GPX4 . Reduced expression of ApoER2 in peripheral blood lymphocytes can contribute to major depressive disorder (MDD) in some patients. Major depressive disorder is the most common psychiatric disorder, where people show symptoms of low self-esteem and a loss of interest in pleasure. By studying the levels of ApoER2 mRNA , low levels of ApoER2 were discovered. Results from experiments have shown that this could be because of transcriptional alterations in lymphocytes. However, low levels of ApoER2 do not appear to correlate with
7350-525: 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
7448-478: 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
7546-443: 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
7644-405: 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
7742-496: 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
7840-500: 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
7938-545: The phosphorylation of a p38MAPkinase , resulting in the production of thromboxane A2 . Thromboxane A2 functions to activate more platelets, and this leads to a greater chance for blood clots to form. There is also speculation that the antibody/β2GPI complexes sensitize other cell types through various LDL family receptors to lead to less common symptoms other than thrombosis. ApoER2 has been found to promote ferroptosis resistance in cancer . Loss of ApoER2 results in insufficient selenium levels, leading to failed translation of
8036-440: 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
8134-424: 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
8232-454: The process of cortical migration. Some studies have shown that reelin release is necessary for the initiation of cell movement to its proper location, whereas others have shown that it is part of the process of terminating migration. These conflicting results have led researchers to speculate that it plays a role in both processes through interactions with different molecules at different stages of neuronal migration . After development, reelin
8330-534: 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,
8428-427: 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
8526-582: 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
8624-573: 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
8722-430: 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
8820-734: The severity or duration of the disease. It only aids as a trait marker in identification of the disease. The impact of the low levels of ApoER2 mRNA function relating to the disease remains unknown. Protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues . Proteins perform 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
8918-419: The signalling ligand responsible for ApoER2's role in modulating the JNK signalling pathway. FE65 is an intracellular protein that binds to the NPXY motif of ApoER2 and plays a role in linking other proteins, such as amyloid precursor protein , to ApoER2. This protein aids in a cell's migrational functions. Knockout studies of FE65 have shown a link to lissencephaly . JIP1 and JIP2 are involved in
9016-405: 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
9114-706: 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
9212-400: 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
9310-472: 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
9408-466: 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
9506-503: Was upregulated in knockout mice lacking both the Vldlr and Apoer2 genes. Inversion of cortical layers, absence of cerebellar foliation, and the migration of Purkinje cells in these animals precisely mimicked the phenotype of mice lacking Reln or Dab1. These findings established novel signaling functions for the LDL receptor gene family and suggested that VLDLR and APOER2 participate in transmitting
9604-581: 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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