1V9U , 3DPR
70-417: 7436 22359 ENSG00000147852 ENSMUSG00000024924 P98155 P98156 NM_001018056 NM_003383 NM_001322225 NM_001322226 NM_001161420 NM_013703 NM_001347441 NP_001018066 NP_001309154 NP_001309155 NP_003374 NP_001154892 NP_001334370 NP_038731 The very-low-density-lipoprotein receptor ( VLDLR ) is a transmembrane lipoprotein receptor of
140-430: A database is that it saves time and power to obtain new effective compounds. Another approach of structure-based drug design is about combinatorially mapping ligands, which is referred to as receptor-based drug design. In this case, ligand molecules are engineered within the constraints of a binding pocket by assembling small pieces in a stepwise manner. These pieces can be either atoms or molecules. The key advantage of such
210-528: A disorganization of neuron ordering in the brain due to disruption of the reelin pathway. The most prominent of these diseases are type I lissencephaly , VLDR-associated cerebellar hypoplasia , and atherosclerosis . In contrast to causing diseases, VLDLR has also been identified as a possible remedy for some disorders. Implementation of VLDLR into the liver may cure familial hypercholesterolemia (FH) in patients who either have defective LDLR or have defective immune systems that attack this protein. Since VLDLR
280-498: A higher conversion rate of plasma triglycerides into epididymal fats. As expected, mice deficient in VLDLR did not show this same response. These results suggest that VLDLR is important in fat accumulation. Many other hormones and dietary factors also regulate VLDLR expression. Thyroid hormone positively regulates VLDLR expression in skeletal muscles of rats, but not in adipose or heart tissues. In rabbits, VLDLR expression in heart muscle
350-477: A knockout in the LDLR gene. In addition, LDLR knockout mice overexpressing VLDLR have decreased serum triglyceride levels. Although fat deposition is close to normal without VLDLR, its role gains importance when LDLR is deficient. Despite this knowledge on its role in lipoprotein uptake, the complete mechanism of lipid metabolism performed by VLDLR is not fully understood. VLDLR is known to employ endocytosis , although
420-476: A low degree of cortical thickening and absence of a cell-sparse zone. The cell-sparse zone describes the region between the outer and inner cortical layers of arrested neurons. In addition, type 1 lissencephaly is closely associated with cerebellar hypoplasia . Disequilibrium syndrome (DES) was first described in the 1970s as a non-progressive, neurological disorder. In a 2005 study, DES was renamed as VLDLR-associated cerebellar hypoplasia (VLDLRCH) after its cause
490-430: A method is that novel structures can be discovered. Beta-propeller In structural biology, a beta-propeller ( β-propeller ) is a type of all-β protein architecture characterized by 4 to 8 highly symmetrical blade-shaped beta sheets arranged toroidally around a central axis. Together the beta-sheets form a funnel-like active site. Each beta-sheet typically has four anti-parallel β-strands arranged in
560-482: A much broader variety of functions in comparison to four- and five-bladed propellers. These functions can include acting as ligand-binding proteins, hydrolases, lyases , isomerases , signaling proteins, structural proteins, and oxidoreductases . Variations in the larger (five- to eight-bladed) beta-propellers can allow for even more specific functions. This is the case with the C-terminal region of GyrA which expresses
630-428: A positively charged surface ideal for binding DNA. Two alpha-helices coming out of the six-bladed beta-propeller of serum paraoxonase may provide a hydrophobic region ideal for anchoring membranes. DNA damage-binding protein 1 has three beta-propellers, in which the connection between two of the propellers is inserted into the third propeller potentially allowing for its unique function. Repeat domains known to fold into
700-556: A pro-atherogenic factor. This characteristic is supported by results from a 2005 study, in which reintroduction of VLDLR into VLDLR knockout mice led to greatly increased atherosclerotic lesion development. Transmembrane receptor Cell surface receptors ( membrane receptors , transmembrane receptors ) are receptors that are embedded in the plasma membrane of cells . They act in cell signaling by receiving (binding to) extracellular molecules . They are specialized integral membrane proteins that allow communication between
770-471: A result of aberrant neuronal migration . In classical type I lissencephaly, neuronal migration begins but is unable to continue to completion. This process is likely disrupted by alterations to several genes, including the VLDLR , DCX , ARX , TUBA1A , RELN and LIS1 . The severity of type I lissencephaly therefore varies with the mutation type. A homozygous deletion affecting the VLDLR gene results in
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#1732876227526840-516: A result of the endocytosis of reelin, or if there is another mechanism at play. In addition to the organization of the neocortex, VLDLR also plays a role in neuronal migration of the hippocampus and the Purkinje cells of the cerebellum . Yet, much information on this process is still unknown. Mutations within the VLDLR gene lead to a multitude of disorders of varying severities. These disorders are usually associated with cholesterol homeostasis or
910-427: A single transmembrane sequence, and a cytoplasmic domain which contains an NPxY sequence. The NPxY motif functions in signal transduction and the targeting of receptors to coated pits and consists of the sequence Asparagine-Proline-X-Tyrosine, where X can be any amino acid. Mimicking this general structure, VLDLR has eight, 40 amino acid long cysteine-rich repeats in its extracellular N-terminal ligand-binding domain. This
980-420: A subviral component to the cytoplasmic side of the cellular membrane. In the case of poliovirus , it is known in vitro that interactions with receptors cause conformational rearrangements which release a virion protein called VP4.The N terminus of VP4 is myristylated and thus hydrophobic【 myristic acid =CH 3 (CH 2 ) 12 COOH】. It is proposed that the conformational changes induced by receptor binding result in
1050-423: A “stop signal.” This is supported by the fact that VLDLR is primarily expressed in the cortical plate adjacent to reelin-expressing cells, Cajal–Retzius cells , and in the intermediate zone. However, definitive evidence has not yet been found. In general, reelin binds VLDLR and undergoes endocytosis via clathrin-coated vesicles . Meanwhile, an intracellular protein, Dab1 , has a PI/PTB domain that interacts with
1120-401: Is about determining ligands for a given receptor. This is usually accomplished through database queries, biophysical simulations, and the construction of chemical libraries. In each case, a large number of potential ligand molecules are screened to find those fitting the binding pocket of the receptor. This approach is usually referred to as ligand-based drug design. The key advantage of searching
1190-419: Is also blocked. VLDLR is found throughout the body, with particularly high expression in fatty acid tissues due to their high level of triglycerides , VLDLR’s primary ligand. These tissues include those of the heart, skeletal muscle, and adipose layer . In addition, the receptor is found in macrophages, endothelial cells of capillaries, and in the brain, where it has a very different function from that found in
1260-411: Is an EGF repeat, a β-propeller segment that plays a role in the pH-dependent dissociation of the ligand-receptor complex, and two more EGF repeats. The VLDLR O-linked glycosylation domain, next in the sequence, has many threonine and serine residues and totals 46 amino acids. The transmembrane domain, which functions in anchoring the receptors to the membrane, is 22 amino acids long. Final in the sequence
1330-550: Is approximately 84% conservation with the respective protein in chickens. This level of homology between species is much higher than that found for LDLR. Hence, these gene comparisons suggest that VLDLR and LDLR diverged before the LDLRs did among vertebrates. VLDLR binds compounds containing apolipoprotein E (apoE). These ligands attach to the cysteine binding repeats in the N-terminus end. The difference in cysteine-rich repeats between
1400-458: Is caused by dysregulation of cholesterol influx and efflux. Since macrophages do not have the ability to limit the influx of cholesterol, the balance is completely dependent on efflux pathways. VLDLR is expressed by macrophages, and functions in the uptake of native lipoproteins . Uniquely, VLDLR does not respond to cholesterol loading, likely due to its lack of feedback mechanisms. The inability to control its uptake of native lipoproteins makes VLDLR
1470-496: Is demonstrated through the alignment of the two receptors according to their linker region; in LDLR, the linker region is located between cysteine-rich repeats four and five of its seven repeats while in VLDLR, the linker region appears to be between repeats five and six of its eight repeats. VLDLR also shows high homology among various species. VLDLR of humans, mice, rats, and rabbits have been identified as 95% identical. Furthermore, there
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#17328762275261540-435: Is displaced by guanosine triphosphate (GTP), thus activating the α subunit, which then dissociates from the β and γ subunits. The activated α subunit can further affect intracellular signaling proteins or target functional proteins directly. If the membrane receptors are denatured or deficient, the signal transduction can be hindered and cause diseases. Some diseases are caused by disorders of membrane receptor function. This
1610-499: Is due to deficiency or degradation of the receptor via changes in the genes that encode and regulate the receptor protein. The membrane receptor TM4SF5 influences the migration of hepatic cells and hepatoma . Also, the cortical NMDA receptor influences membrane fluidity, and is altered in Alzheimer's disease. When the cell is infected by a non-enveloped virus, the virus first binds to specific membrane receptors and then passes itself or
1680-631: Is encoded by two SRE-1-like sequences that contain single nucleotide polymorphisms . These polymorphisms disrupt the SREBP-1 binding to the CAC repeats, and hence eliminate the feedback mechanism seen in other proteins. VLDLR expression is regulated by peroxisome proliferator-activated receptor-gamma (PPAR-γ). A 2010 study showed that the prescription drug Pioglitazone , an agonist of PPAR-γ, increases VLDLR mRNA expression and protein levels in experiments using mouse fibroblasts. The Pioglitazone treated mice exhibited
1750-714: Is evidence of a cytosine to thymine transition at base pair number 769 in exon 5 that causes a substitution at Arg 257 for a termination signal. A third known mutation is caused by a homozygous 1-base pair deletion in exon 17 that causes a frameshift and premature termination in the O-linked sugar domain. All such alterations to the VLDLR gene prevent the production of VLDLR and are therefore termed loss-of-function mutations. The recognized symptoms of VLDLRCH are moderate-to-severe intellectual disability, seizures, dysarthria , strabismus and delayed locomotion. In some cases, children with VLDLRCH learn to walk very late in development after
1820-398: Is non-immunogenic it does not initiate an immune response, thus it is able to function normally under defective immune systems. In addition, being that apoE , a major ligand of VLDLR, is a leading genetic risk factor for Alzheimer’s disease , VLDLR may play a role in modulating the risk of this disorder which is explained by the fact that a decrease in reelin signaling in the fascia dentata
1890-425: Is primarily responsible for the correct layering of pyramidal cells into layer 1 of the cerebral cortex . In particular, the absence of VLDLR may lead to ectopic accumulation of pyramidal cells in this region. VLDLR does not affect the migration of early born cells into an organized layer, but since its absence results in the invasion of these neuroblasts into the marginal zone, it is theorized that VLDLR may encode
1960-403: Is restricted to the cortex and cerebellum. Here, the receptor can be found on resting or activated microglia that are associated with senile plaques and cortical neurons, neuroblasts , matrix cells, Cajal-Retzius cells , glioblasts , astrocytes , oligodendrocytes , and region-specific pyramidal neurons . Despite its major role in cholesterol and fatty acid metabolism, VLDLR is not found in
2030-408: Is supposed to initiate Alzheimer's disease. VLDLR has also been shown to reduce the chances of premature heart disease and stroke because VLDLR clears out lipoprotein A (Lp(a)), a major inherited risk factor for these diseases. Type I lissencephaly , or agyria-pachygyria, is a rare developmental disorder characterized by the absence of gyri and sulci in the brain. These severe malformations are
2100-449: Is the 54 amino acid cytoplasmic domain, which contains the NPxY motif. The full-length human VLDLR genome is located on locus 9p24 on chromosome 9. It consists of a 40 kb segment that includes 19 exon -coding sequences, which is one more exon than encoded by LDLR . This extra exon in the VLDLR gene accounts for the extra cysteine-binding repeat not found in LDLR. Together, the exons making up
2170-466: Is the main difference from the main member of the LDL receptor family, LDLR , which has only seven cysteine-rich repeats which are also 40 amino acids long. Each of these cysteine-rich repeats, in both VLDLR and LDLR, has three disulfide bonds and a coordinated Ca ion. The N-terminus also consists of a glycine residue followed by 27 hydrophobic residues that constitute the signal peptide . Following this region
VLDL receptor - Misplaced Pages Continue
2240-440: Is the native protein conformation. As two molecules of acetylcholine both bind to the binding sites on α subunits, the conformation of the receptor is altered and the gate is opened, allowing for the entry of many ions and small molecules. However, this open and occupied state only lasts for a minor duration and then the gate is closed, becoming the closed and occupied state. The two molecules of acetylcholine will soon dissociate from
2310-402: Is up-regulated by estrogen and down-regulated by granulocyte-macrophage colony-stimulating factor . In trophoblast -derived cell lines, up-regulated VLDLR expression occurs when cells are incubated with hypolipidemic agents such as insulin and clofibrate . In contrast, 8-bromoadenosine 3',5'-cyclic monophosphate (8-bromo-cAMP) down-regulates VLDLR expression. Finally, VLDLR is affected by
2380-420: The 7TM superfamily , the transmembrane domain includes a ligand binding pocket. The intracellular (or cytoplasmic ) domain of the receptor interacts with the interior of the cell or organelle, relaying the signal. There are two fundamental paths for this interaction: Signal transduction processes through membrane receptors involve the external reactions, in which the ligand binds to a membrane receptor, and
2450-486: The LDL receptor family . In particular, there is 50% overall sequence homology between VLDLR and ApoER2 , another lipoprotein receptor of this family. Comparing LDLR and VLDLR, it was found that their primary structures are 55% identical within their ligand -binding regions. The modular structures of these two proteins are almost superimposable, with the only difference being the additional cysteine-rich repeat in VLDLR. This
2520-510: The VLDLR gene encode a protein that is 873 amino acid residues long. VLDLR is known to exist as four different protein isoforms : type I, II, III, and IV. These different isoforms result from variations in alternative splicing . The transcript of type I VLDLR (VLDLR-I) is composed of all 19 exons. VLDLR-II, on the other hand, lacks exon 16, which encodes for the O-glycosylation domain between sugar regions. VLDLR-III lacks exon 4 that encodes
2590-557: The cerebellum , where VLDLR is believed to be most prominent. VLDLR is expressed on migrating neurons to help guide them to their proper location in the brain. This process is part of the reelin pathway, which is responsible for the inside-out formation of the six-layered neocortex . Despite the discovery of this pathway, many of the specifics and molecular mechanisms of this process are still being debated. The presence of two reelin receptors, VLDLR and ApoER2 , has made it difficult to distinguish each protein’s specific function. VLDLR
2660-723: The epidermal growth factor (EGF) receptor binds with its ligand EGF, the two receptors dimerize and then undergo phosphorylation of the tyrosine residues in the enzyme portion of each receptor molecule. This will activate the tyrosine kinase and catalyze further intracellular reactions. G protein-coupled receptors comprise a large protein family of transmembrane receptors. They are found only in eukaryotes . The ligands which bind and activate these receptors include: photosensitive compounds, odors , pheromones , hormones , and neurotransmitters . These vary in size from small molecules to peptides and large proteins . G protein-coupled receptors are involved in many diseases, and thus are
2730-492: The low-density-lipoprotein (LDL) receptor family . VLDLR shows considerable homology with the members of this lineage. Discovered in 1992 by T. Yamamoto, VLDLR is widely distributed throughout the tissues of the body, including the heart, skeletal muscle , adipose tissue , and the brain, but is absent from the liver. This receptor has an important role in cholesterol uptake, metabolism of apolipoprotein E -containing triacylglycerol -rich lipoproteins, and neuronal migration in
2800-454: The lysosome . At this point, hydrolysis occurs and lipoprotein is released into the cytoplasm while the receptors are recycled back to the cell surface. It is not yet confirmed if VLDLR follows this exact mechanism, but one closely related to it is likely. In addition to its role throughout the body, VLDLR has a unique role in the brain. It is a key component of the reelin pathway, which functions on one hand side in neuronal migration during
2870-444: The nicotinic acetylcholine receptor , the transmembrane domain forms a protein pore through the membrane, or around the ion channel . Upon activation of an extracellular domain by binding of the appropriate ligand, the pore becomes accessible to ions, which then diffuse. In other receptors, the transmembrane domains undergo a conformational change upon binding, which affects intracellular conditions. In some receptors, such as members of
VLDL receptor - Misplaced Pages Continue
2940-491: The reelin pathway, as THBS1 can block the attachment of reelin, while simultaneously stimulating the transcription factors normally activated by reelin. This binding of THBS1, however, does not induce the subsequent degradation of these transcription factors, as reelin does, and can thus lead to greatly amplified effects. The RAP protein acts similarly by blocking reelin from binding VLDLR. However, in this case phosphorylation of transcription factors, usually performed by reelin,
3010-400: The sterol regulatory element-1 (SRE-1) of VLDLR. Normal SRE-1 sequences, like those found in LDLR, are characterized by two repeats of the codon CAC separated by two intervening C nucleotides (5’-CACCCCAC-3’). The sterol regulatory element-binding protein -1 (SREBP-1), a transcription factor , targets the CAC repeats of SRE-1 to regulate the protein’s transcription. However, the VLDLR gene
3080-413: The NPxY sequence found in the cytoplasmic tail of VLDLR. As a result, Dab1 is tyrosine phosphorylated and reelin is degraded. Finally, phosphorylated Dab1 activates an intracellular signaling cascade that directs neuroblasts to their proper location through the alteration of the cytoskeleton . Many of the specifics of this pathway are still being investigated. It is not yet known if Dab1 is phosphorylated as
3150-553: The age of six years, or never learn to walk independently. The frequency of this disorder is unknown because early diagnosis of VLDLRCH is difficult using imaging techniques. It is associated with parental consanguinity and found in secluded communities such as the Hutterites and inbred families from Iran and Turkey. Atherosclerosis is marked by an excessive accumulation of cholesterol by macrophages , leading to their transformation into foam cells . This accumulation of cholesterol
3220-509: The attachment of myristic acid on VP4 and the formation of a channel for RNA. Through methods such as X-ray crystallography and NMR spectroscopy , the information about 3D structures of target molecules has increased dramatically, and so has structural information about the ligands. This drives rapid development of structure-based drug design . Some of these new drugs target membrane receptors. Current approaches to structure-based drug design can be divided into two categories. The first category
3290-598: The beta-sheets of the C- and N-terminal ends. In effect this closes the circle which can occur even more strongly in 4-bladed proteins via a disulfide bond. The chaperones Hsp70 and CCT have been shown to sequentially bind nascent beta-propellers as they emerge from the ribosome. These chaperones prevent non-native inter-blade interactions from forming until the entire beta-propeller is synthesized. Many beta-propellers are dependent on CCT for expression. In at least one case, ions have been shown to increase stability by binding deep in
3360-414: The beta-zigzag motif. The strands are twisted so that the first and fourth strands are almost perpendicular to each other. There are five classes of beta-propellers, each arrangement being a highly symmetrical structure with 4–8 beta sheets, all of which generally form a central tunnel that yields pseudo-symmetric axes. While, the protein's official active site for ligand-binding is formed at one end of
3430-540: The bilayer several times, the external domain comprises loops entwined through the membrane. By definition, a receptor's main function is to recognize and respond to a type of ligand. For example, a neurotransmitter , hormone , or atomic ions may each bind to the extracellular domain as a ligand coupled to receptor. Klotho is an enzyme which effects a receptor to recognize the ligand ( FGF23 ). Two most abundant classes of transmembrane receptors are GPCR and single-pass transmembrane proteins . In some receptors, such as
3500-482: The bloodstream, where it may be used in cellular membranes. In addition, it will allow fatty acids to get into cells where they may be used as an energy source. Overall, VLDLR primarily modulates the extra- hepatic metabolism of triglyceride -rich lipoproteins. VLDLR only plays a discrete role in lipid metabolism, but is more significant in stressed situations. Mice with double knockouts in VLDLR and LDLR have higher serum triglyceride levels than those with only
3570-714: The cell and the extracellular space . The extracellular molecules may be hormones , neurotransmitters , cytokines , growth factors , cell adhesion molecules , or nutrients ; they react with the receptor to induce changes in the metabolism and activity of a cell. In the process of signal transduction , ligand binding affects a cascading chemical change through the cell membrane. Many membrane receptors are transmembrane proteins . There are various kinds, including glycoproteins and lipoproteins . Hundreds of different receptors are known and many more have yet to be studied. Transmembrane receptors are typically classified based on their tertiary (three-dimensional) structure. If
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#17328762275263640-451: The central tunnel by loops between individual beta-strands, protein-protein interactions can occur at multiple areas around the domain. Depending on the packing and tilt of the beta-sheets and beta-strands, the beta-propeller may have a central pocket in place of a tunnel. The beta-propeller structure is stabilized mainly through hydrophobic interactions of the beta-sheets, while additional stability may come from hydrogen bonds formed between
3710-516: The central tunnel of the beta-propeller. Murzin proposed a geometric model to describe the structural principles of the beta propeller. According to this model the seven bladed propeller was the most favored arrangement in geometric terms. Despite its highly conserved nature, beta-propellers are well known for their plasticity. Beyond having a variety of allowed beta-sheets per domain, it can also accommodate other domains into its beta-sheets. Additionally, there are proteins that have shown variance in
3780-655: The developing brain. In humans, VLDLR is encoded by the VLDLR gene. Mutations of this gene may lead to a variety of symptoms and diseases, which include type I lissencephaly , cerebellar hypoplasia , and atherosclerosis . VLDLR is a member of the low-density-lipoprotein (LDL) receptor family , which is entirely composed of type I transmembrane lipoprotein receptors. All members of this family share five highly conserved structural domains: an extracellular N-terminal ligand -binding domain with cysteine-rich repeats (also called ligand-binding repeats), an epidermal growth factor (EGF), an O-linked glycosylation sugar domain,
3850-446: The development of the brain, on the other hand in the retention of new memory traces in the hippocampal formation . VLDLR links the reelin protein to an intracellular signaling protein, Dab1 , that tells the individual neurons where to go within the anatomy of the brain. Mutations in VLDLR often do not lead to major disorganization as seen in reelin mutations. However, a VLDLR mutation does lead to some disorganization primarily located in
3920-494: The exact mechanism of this process is unknown for this protein. Endocytosis is mediated through NPxY sequences known to signal for receptor internalization through clathrin-coated pits . The presence of this sequence in the cytoplasmic tail of VLDLR makes endocytosis possible. In general, lipoprotein receptors undergo a process by which they are endocytosed with their ligand into clathrin-coated pits. From here, they are together transported to early and late endosomes until reaching
3990-408: The internal reactions, in which intracellular response is triggered. Signal transduction through membrane receptors requires four parts: Membrane receptors are mainly divided by structure and function into 3 classes: The ion channel linked receptor ; The enzyme-linked receptor ; and The G protein-coupled receptor . During the signal transduction event in a neuron, the neurotransmitter binds to
4060-406: The liver. This phenomenon is mainly attributed to the very high levels of LDLR in these areas. In addition, it has been uncovered that this receptor is found, sub-cellularly, in the non- lipid raft sections of cell membranes. Unlike LDLR , VLDLR does not exhibit any feedback mechanism, and hence intracellular lipoproteins are incapable of regulating it. This phenomenon is due to a difference in
4130-555: The members of the LDL receptor family lead to the differences in binding affinity. VLDLR, in particular, binds VLDL and intermediate-density lipoprotein (IDL), but not LDL . This inability to bind LDL is due to VLDLR's incapability to bind apolipoprotein B (apoB), which is present in LDL. Receptor-associated protein (RAP) and thrombospondin-1 (THBS1) have been identified as compounds that bind VLDLR. In many cases, these compounds exhibit inhibitory effects. THBS1 binds VLDLR and blocks ligand binding. This plays an important role in
4200-432: The number of beta-strands per beta-sheet. Rather than having the typical four beta-strands in a sheet, beta-lactamase inhibitor protein -II only has three beta-strands per sheet while the phytase of Bacillus subtilis has five beta-strands per beta-sheet. Due to its structure and plasticity, protein-protein interactions can form with the top, bottom, central channel, and side faces of the beta-propeller. The function of
4270-454: The presence of apoE and LDLR. The presence of apoE is required for VLDLR expression regulation, while the absence of LDLR alters the sterol -regulatory-element-1-like sequences of VLDLR to make them functional in only heart and skeletal muscle. VLDLR is a peripheral lipoprotein receptor that functions in lipoprotein metabolism, cardiac fatty acid metabolism, and fat deposition. In effect, VLDLR will allow cholesterol to reach tissues from
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#17328762275264340-533: The propeller can vary based on the blade number. Four-bladed beta-propellers function mainly as transport proteins , and because of its structure, they have a conformation that is favorable for substrate binding. Unlike larger beta-propellers, four-bladed beta-propellers usually cannot perform catalysis themselves, but act instead to aid in catalysis by performing the aforementioned functions. Five-bladed propellers can act as transferases , hydrolases , and sugar binding proteins. Six- and seven-bladed propellers perform
4410-628: The receptor and alters the conformation of the protein. This opens the ion channel, allowing extracellular ions into the cell. Ion permeability of the plasma membrane is altered, and this transforms the extracellular chemical signal into an intracellular electric signal which alters the cell excitability . The acetylcholine receptor is a receptor linked to a cation channel. The protein consists of four subunits: alpha (α), beta (β), gamma (γ), and delta (δ) subunits. There are two α subunits, with one acetylcholine binding site each. This receptor can exist in three conformations. The closed and unoccupied state
4480-859: The receptor, returning it to the native closed and unoccupied state. As of 2009, there are 6 known types of enzyme-linked receptors : Receptor tyrosine kinases ; Tyrosine kinase associated receptors; Receptor-like tyrosine phosphatases ; Receptor serine / threonine kinases ; Receptor guanylyl cyclases and histidine kinase associated receptors. Receptor tyrosine kinases have the largest population and widest application. The majority of these molecules are receptors for growth factors such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), nerve growth factor (NGF) and hormones such as insulin . Most of these receptors will dimerize after binding with their ligands, in order to activate further signal transductions. For example, after
4550-408: The rest of the body. There is a preferred expression for VLDLR type I in the heart, skeletal muscle and brain, as opposed to type II, which is mainly expressed in non-muscular tissues including the cerebrum , cerebellum , kidney, spleen, and aortic endothelial cells. The highest expression of VLDLR is found in the brain. Although VLDLR is found in almost all regions of the brain, its highest expression
4620-418: The sort of membrane and cellular function. Receptors are often clustered on the membrane surface, rather than evenly distributed. Two models have been proposed to explain transmembrane receptors' mechanism of action. Transmembrane receptors in plasma membrane can usually be divided into three parts. The extracellular domain is just externally from the cell or organelle . If the polypeptide chain crosses
4690-506: The targets of many modern medicinal drugs. There are two principal signal transduction pathways involving the G-protein coupled receptors: the cAMP signaling pathway and the phosphatidylinositol signaling pathway. Both are mediated via G protein activation. The G-protein is a trimeric protein, with three subunits designated as α, β, and γ. In response to receptor activation, the α subunit releases bound guanosine diphosphate (GDP), which
4760-485: The third ligand -binding repeat. Finally, VLDLR-IV transcripts lack both exon 16 and exon 4. It has been shown that 75% of VLDLR transcripts exist as isoform type II in mouse brain models. This shows that most VLDLRs in the brain are not glycosylated, as type II lacks exon 16 which encodes the O-glycosylation domain. Isoform type IV is known to be the second most prominent. There is a high level of conservation within
4830-517: The three-dimensional structure is unknown, they can be classified based on membrane topology . In the simplest receptors, polypeptide chains cross the lipid bilayer once, while others, such as the G-protein coupled receptors , cross as many as seven times. Each cell membrane can have several kinds of membrane receptors, with varying surface distributions. A single receptor may also be differently distributed at different membrane positions, depending on
4900-438: Was linked to a disruption in the VLDLR gene. At least six mutations affecting the homozygous recessive allele of the VLDLR gene have been identified and found to cause VLDLRCH. Several of these mutations have been localized to specific exons encoding the gene. One such mutation is a cytosine to thymine transition at base pair 1342 in exon 10 that causes a substitution at Arg 448 for a termination signal . Likewise, there
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