Wikipedia

VLDL receptor

Thevery-low-density-lipoprotein receptor(VLDLR) is atransmembranelipoproteinreceptor of thelow-density-lipoprotein (LDL) receptor family.VLDLR shows considerablehomologywith 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.[5]This receptor has an important role in cholesterol uptake, metabolism ofapolipoprotein E-containingtriacylglycerol-rich lipoproteins, andneuronal migrationin the developing brain. In humans, VLDLR is encoded by theVLDLRgene. Mutations of this gene may lead to a variety of symptoms and diseases, which include type Ilissencephaly,cerebellar hypoplasia,andatherosclerosis.

VLDLR
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesVLDLR,CAMRQ1, CARMQ1, CHRMQ1, VLDLRCH, VLDL-R, very low density lipoprotein receptor
External IDsOMIM:192977;MGI:98935;HomoloGene:443;GeneCards:VLDLR;OMA:VLDLR - orthologs
Orthologs
SpeciesHumanMouse
Entrez

7436

22359

Ensembl

ENSG00000147852

ENSMUSG00000024924

UniProt

P98155

P98156

RefSeq (mRNA)

NM_001018056
NM_003383
NM_001322225
NM_001322226

NM_001161420
NM_013703
NM_001347441

RefSeq (protein)

NP_001018066
NP_001309154
NP_001309155
NP_003374

NP_001154892
NP_001334370
NP_038731

Location (UCSC)Chr 9: 2.62 – 2.66 MbChr 19: 27.22 – 27.25 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Protein structure

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VLDLR is a member of thelow-density-lipoprotein (LDL) receptor family,which is entirely composed of type Itransmembranelipoproteinreceptors.

The structural differences of the LDL receptor family. This image represents the similarities in structural domains among the members, as well as the extra cysteine repeat present on the VLDL receptor.

All members of this family share five highly conserved structural domains: an extracellular N-terminalligand-binding domain with cysteine-rich repeats (also called ligand-binding repeats), anepidermal growth factor(EGF), anO-linked glycosylationsugar domain, 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.[6]Mimicking this general structure, VLDLR has eight, 40 amino acid long cysteine-rich repeats in its extracellular N-terminal ligand-binding domain.[6]This 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.[7]Each of these cysteine-rich repeats, in both VLDLR and LDLR, has three disulfide bonds and a coordinated Ca2+ion. The N-terminus also consists of a glycine residue followed by 27hydrophobicresidues that constitute thesignal peptide.[6]Following this region is an EGF repeat, aβ-propellersegment that plays a role in the pH-dependent dissociation of the ligand-receptor complex,[8]and two more EGF repeats.[9]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.[6]Final in the sequence is the 54 amino acid cytoplasmic domain, which contains the NPxY motif.[8]

Isoforms

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The full-length human VLDLR genome is located on locus 9p24 on chromosome 9. It consists of a 40 kb segment that includes 19exon-coding sequences, which is one more exon than encoded byLDLR.This extra exon in theVLDLRgene accounts for the extra cysteine-binding repeat not found in LDLR.[7]Together, the exons making up theVLDLRgene encode a protein that is 873 amino acid residues long. VLDLR is known to exist as four differentprotein isoforms:type I, II, III, and IV. These different isoforms result from variations inalternative 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 theO-glycosylationdomain between sugar regions. VLDLR-III lacks exon 4 that encodes the thirdligand-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 inmouse brainmodels. 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.[6]

Evolutionary conservation

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There is a high level of conservation within theLDL receptor family.In particular, there is 50% overall sequencehomologybetween VLDLR andApoER2,anotherlipoproteinreceptor of this family.[6]ComparingLDLRand VLDLR, it was found that theirprimary structuresare 55% identical within theirligand-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 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.[10]

VLDLR also shows high homology among various species. VLDLR of humans, mice, rats, and rabbits have been identified as 95% identical. Furthermore, there 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.[10]

Ligand binding

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VLDLR binds compounds containingapolipoprotein E(apoE). Theseligandsattach to the cysteine binding repeats in the N-terminus end. The difference in cysteine-rich repeats between the members of theLDL receptor familylead to the differences in binding affinity. VLDLR, in particular, bindsVLDLandintermediate-density lipoprotein(IDL), but notLDL.This inability to bind LDL is due to VLDLR's incapability to bindapolipoprotein B(apoB), which is present in LDL.[11]

Inhibitors

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Receptor-associated protein(RAP) andthrombospondin-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.[11]This plays an important role in thereelinpathway, as THBS1 can block the attachment of reelin, while simultaneously stimulating thetranscription factorsnormally 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.[6]The RAP protein acts similarly by blocking reelin from binding VLDLR. However, in this case phosphorylation of transcription factors, usually performed by reelin, is also blocked.[12]

Tissue distribution and expression

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VLDLR is found throughout the body, with particularly high expression in fatty acid tissues due to their high level oftriglycerides,VLDLR’s primary ligand. These tissues include those of the heart, skeletal muscle, andadipose layer.In addition, the receptor is found in macrophages, endothelial cells of capillaries,[8]and in the brain, where it has a very different function from that found in 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 thecerebrum,cerebellum,kidney, spleen, and aortic endothelial cells.[7][11]The highest expression of VLDLR is found in the brain. Although VLDLR is found in almost all regions of the brain, its highest expression is restricted to the cortex and cerebellum. Here, the receptor can be found on resting or activatedmicrogliathat are associated withsenile plaquesand cortical neurons,neuroblasts,matrix cells,Cajal-Retzius cells,glioblasts,astrocytes,oligodendrocytes,and region-specificpyramidal neurons.[6]Despite its major role in cholesterol and fatty acid metabolism, VLDLR is not found in the liver. This phenomenon is mainly attributed to the very high levels ofLDLRin these areas.[7]In addition, it has been uncovered that this receptor is found, sub-cellularly, in the non-lipid raftsections of cell membranes.[6]

Regulation

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UnlikeLDLR,VLDLR does not exhibit any feedback mechanism, and hence intracellularlipoproteinsare incapable of regulating it. This phenomenon is due to a difference in thesterolregulatory 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’). Thesterol regulatory element-binding protein-1 (SREBP-1), atranscription factor,targets the CAC repeats of SRE-1 to regulate the protein’s transcription. However, theVLDLRgene is encoded by two SRE-1-like sequences that containsingle nucleotide polymorphisms.These polymorphisms disrupt the SREBP-1 binding to the CAC repeats, and hence eliminate the feedback mechanism seen in other proteins.[7]

VLDLR expression is regulated byperoxisome proliferator-activated receptor-gamma(PPAR-γ). A 2010 study showed that the prescription drugPioglitazone,anagonistof PPAR-γ, increases VLDLR mRNA expression and protein levels in experiments using mouse fibroblasts. The Pioglitazone treated mice exhibited a higher conversion rate of plasmatriglyceridesinto epididymal fats. As expected, mice deficient in VLDLR did not show this same response.[8]These results suggest that VLDLR is important in fat accumulation.[8]

Many other hormones and dietary factors also regulate VLDLR expression.Thyroid hormonepositively regulates VLDLR expression in skeletal muscles of rats, but not in adipose or heart tissues. In rabbits, VLDLR expression in heart muscle is up-regulated by estrogen and down-regulated bygranulocyte-macrophage colony-stimulating factor.Introphoblast-derived cell lines, up-regulated VLDLR expression occurs when cells are incubated withhypolipidemic agentssuch asinsulinandclofibrate.In contrast,8-bromoadenosine 3',5'-cyclic monophosphate(8-bromo-cAMP) down-regulates VLDLR expression. Finally, VLDLR is affected by the presence ofapoEand LDLR. The presence of apoE is required for VLDLR expression regulation, while the absence of LDLR alters thesterol-regulatory-element-1-like sequences of VLDLR to make them functional in only heart and skeletal muscle.[7]

Function

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Beyond the nervous system

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VLDLR is a peripherallipoproteinreceptor that functions in lipoprotein metabolism, cardiacfatty acidmetabolism, and fat deposition. In effect, VLDLR will allowcholesterolto reach tissues from 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.[7]Overall, VLDLR primarily modulates the extra-hepaticmetabolism oftriglyceride-rich lipoproteins.[8]

Lipoprotein uptake

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VLDLR only plays a discrete role in lipid metabolism, but is more significant in stressed situations. Mice with doubleknockoutsinVLDLRandLDLRhave higher serumtriglyceridelevels than those with only a knockout in theLDLRgene. In addition,LDLRknockout 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.[11]

Endocytosis
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VLDLR is known to employendocytosis,although the exact mechanism of this process is unknown for this protein. Endocytosis is mediated through NPxY sequences known to signal for receptor internalization throughclathrin-coated pits.The presence of this sequence in the cytoplasmic tail of VLDLR makes endocytosis possible.[11]In general,lipoproteinreceptors undergo a process by which they are endocytosed with their ligand into clathrin-coated pits. From here, they are together transported to early and lateendosomesuntil reaching thelysosome.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.[8]

In the nervous system

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The reelin pathway, representing VLDLR’s role in the process.

In addition to its role throughout the body, VLDLR has a unique role in the brain. It is a key component of thereelinpathway, which functions on one hand side inneuronal migrationduring the development of the brain, on the other hand in the retention of new memory traces in thehippocampal formation.[13][14]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 thecerebellum,where VLDLR is believed to be most prominent.[6]

Neuronal migration

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VLDLR is expressed on migrating neurons to help guide them to their proper location in the brain. This process is part of thereelinpathway, which is responsible for the inside-out formation of the six-layeredneocortex.[6]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 andApoER2,has made it difficult to distinguish each protein’s specific function.[15]

Organization of the six layered neocortex. In the absence of VLDLR, the neuroblasts of the cortical plate invade the marginal zone above.

VLDLR is primarily responsible for the correct layering ofpyramidal cellsinto layer 1 of thecerebral cortex.In particular, the absence of VLDLR may lead to ectopic accumulation of pyramidal cells in this region.[15]VLDLR does not affect the migration of early born cells into an organized layer, but since its absence results in the invasion of theseneuroblastsinto the marginal zone, it is theorized that VLDLR may encode 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.[6]In general, reelin binds VLDLR and undergoesendocytosisviaclathrin-coated vesicles.[6]Meanwhile, an intracellular protein,Dab1,has aPI/PTB domainthat interacts with the NPxY sequence found in the cytoplasmic tail of VLDLR.[12]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 thecytoskeleton.[12][16]Many of the specifics of this pathway are still being investigated. It is not yet known if Dab1 is phosphorylated as 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 thehippocampusand thePurkinje cellsof thecerebellum.Yet, much information on this process is still unknown.[6]

Associated disorders

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Mutations within theVLDLRgene lead to a multitude of disorders of varying severities. These disorders are usually associated withcholesterolhomeostasisor a disorganization of neuron ordering in the brain due to disruption of thereelinpathway. The most prominent of these diseases are type Ilissencephaly,VLDR-associatedcerebellar hypoplasia,andatherosclerosis.In contrast to causing diseases, VLDLR has also been identified as a possible remedy for some disorders. Implementation of VLDLR into the liver may curefamilial hypercholesterolemia(FH) in patients who either have defectiveLDLRor have defective immune systems that attack this protein. Since VLDLR is non-immunogenic it does not initiate an immune response, thus it is able to function normally under defective immune systems.[7]In addition, being thatapoE,a major ligand of VLDLR, is a leading genetic risk factor forAlzheimer’s disease,VLDLR may play a role in modulating the risk of this disorder[6]which is explained by the fact that a decrease in reelin signaling in thefascia dentatais supposed to initiate Alzheimer's disease.[17]VLDLR has also been shown to reduce the chances of premature heart disease and stroke because VLDLR clears outlipoprotein A(Lp(a)), a major inherited risk factor for these diseases.[7]

Type 1 lissencephaly

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Type Ilissencephaly,or agyria-pachygyria, is a rare developmental disorder characterized by the absence ofgyriandsulciin the brain. These severe malformations are a result of aberrantneuronal 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 theVLDLR,DCX,ARX,TUBA1A,RELNandLIS1.The severity of type I lissencephaly therefore varies with the mutation type. A homozygous deletion affecting theVLDLRgene results in 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.[18]In addition, type 1 lissencephaly is closely associated withcerebellar hypoplasia.

VLDLR-associated cerebellar hypoplasia

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Disequilibrium syndrome (DES) was first described in the 1970s as a non-progressive, neurological disorder.[19]In a 2005 study, DES was renamed asVLDLR-associated cerebellar hypoplasia(VLDLRCH) after its cause was linked to a disruption in theVLDLRgene.[20]At least six mutations affecting the homozygous recessive allele of theVLDLRgene have been identified and found to cause VLDLRCH. Several of these mutations have been localized to specificexonsencoding the gene. One such mutation is acytosinetothyminetransition at base pair 1342 in exon 10 that causes a substitution atArg448 for atermination signal.Likewise, there is evidence of a cytosine to thymine transition at base pair number 769 in exon 5 that causes a substitution atArg257 for a termination signal. A third known mutation is caused by a homozygous 1-base pair deletion in exon 17 that causes aframeshiftand premature termination in theO-linked sugardomain.[21]All such alterations to theVLDLRgene 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,strabismusand delayed locomotion. In some cases, children with VLDLRCH learn to walk very late in development after 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 parentalconsanguinityand found in secluded communities such as theHutteritesand inbred families from Iran and Turkey.[22]

Atherosclerosis

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Atherosclerosisis marked by an excessive accumulation ofcholesterolbymacrophages,leading to their transformation intofoam cells.This accumulation of cholesterol 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 nativelipoproteins.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 a pro-atherogenic factor.[23]This characteristic is supported by results from a 2005 study, in which reintroduction of VLDLR intoVLDLRknockout mice led to greatly increased atherosclerotic lesion development.[23]

See also

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References

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  1. ^abcGRCh38: Ensembl release 89: ENSG00000147852–Ensembl,May 2017
  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000024924–Ensembl,May 2017
  3. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^Nimpf J, Schneider WJ (December 2000). "From cholesterol transport to signal transduction: low density lipoprotein receptor, very low density lipoprotein receptor, and apolipoprotein E receptor-2".Biochim. Biophys. Acta.1529(1–3): 287–98.doi:10.1016/S1388-1981(00)00155-4.PMID11111096.
  6. ^abcdefghijklmnoReddy SS, Connor TE, Weeber EJ, Rebeck W (2011)."Similarities and differences in structure, expression, and functions of VLDLR and ApoER2".Mol Neurodegener.6:30.doi:10.1186/1750-1326-6-30.PMC3113299.PMID21554715.
  7. ^abcdefghiTakahashi S, Sakai J, Fujino T, Hattori H, Zenimaru Y, Suzuki J, Miyamori I, Yamamoto TT (2004)."The very low-density lipoprotein (VLDL) receptor: characterization and functions as a peripheral lipoprotein receptor".J. Atheroscler. Thromb.11(4): 200–8.doi:10.5551/jat.11.200.PMID15356379.
  8. ^abcdefgGo GW, Mani A (March 2012)."Low-density lipoprotein receptor (LDLR) family orchestrates cholesterol homeostasis".Yale J Biol Med.85(1): 19–28.PMC3313535.PMID22461740.
  9. ^Tissir F, Goffinet AM (June 2003). "Reelin and brain development".Nat. Rev. Neurosci.4(6): 496–505.doi:10.1038/nrn1113.PMID12778121.S2CID12039624.
  10. ^abNimpf J, Schneider WJ (December 1998)."The VLDL receptor: an LDL receptor relative with eight ligand binding repeats, LR8".Atherosclerosis.141(2): 191–202.doi:10.1016/s0021-9150(98)00172-5.PMID9862168.
  11. ^abcdeGUPEA: Mechanisms for and consequences of cellular lipid accumulation - Role of the Very Low Density Lipoprotein (VLDL) receptor.2011-12-02.hdl:2077/27815.ISBN9789162883560.
  12. ^abcRice DS, Curran T (2001). "Role of the reelin signaling pathway in central nervous system development".Annu. Rev. Neurosci.24:1005–39.doi:10.1146/annurev.neuro.24.1.1005.PMID11520926.S2CID17258257.
  13. ^Kovács KA (September 2020)."Episodic Memories: How do the Hippocampus and the Entorhinal Ring Attractors Cooperate to Create Them?".Frontiers in Systems Neuroscience.14:68.doi:10.3389/fnsys.2020.559186.PMC7511719.PMID33013334.
  14. ^Kovács KA (December 2021)."Relevance of a Novel Circuit-Level Model of Episodic Memories to Alzheimer's Disease".International Journal of Molecular Sciences.23(1): 462.doi:10.3390/ijms23010462.PMC8745479.PMID35008886.
  15. ^abValiente M, Marín O (February 2010). "Neuronal migration mechanisms in development and disease".Curr. Opin. Neurobiol.20(1): 68–78.doi:10.1016/j.conb.2009.12.003.PMID20053546.S2CID18658808.
  16. ^Bielas S, Higginbotham H, Koizumi H, Tanaka T, Gleeson JG (2004). "Cortical neuronal migration mutants suggest separate but intersecting pathways".Annu. Rev. Cell Dev. Biol.20:593–618.doi:10.1146/annurev.cellbio.20.082503.103047.PMID15473853.
  17. ^Kovács KA (December 2021)."Relevance of a Novel Circuit-Level Model of Episodic Memories to Alzheimer's Disease".International Journal of Molecular Sciences.23(1): 462.doi:10.3390/ijms23010462.PMC8745479.PMID35008886.
  18. ^Spalice A, Parisi P, Nicita F, Pizzardi G, Del Balzo F, Iannetti P (March 2009)."Neuronal migration disorders: clinical, neuroradiologic and genetics aspects".Acta Paediatr.98(3): 421–33.doi:10.1111/j.1651-2227.2008.01160.x.PMID19120042.S2CID21620197.
  19. ^Moheb LA, Tzschach A, Garshasbi M, Kahrizi K, Darvish H, Heshmati Y, Kordi A, Najmabadi H, Ropers HH, Kuss AW (February 2008)."Identification of a nonsense mutation in the very low-density lipoprotein receptor gene (VLDLR) in an Iranian family with dysequilibrium syndrome".Eur. J. Hum. Genet.16(2): 270–3.doi:10.1038/sj.ejhg.5201967.PMID18043714.
  20. ^Boycott KM, Flavelle S, Bureau A, Glass HC, Fujiwara TM, Wirrell E, Davey K, Chudley AE, Scott JN, McLeod DR, Parboosingh JS (September 2005)."Homozygous deletion of the very low density lipoprotein receptor gene causes autosomal recessive cerebellar hypoplasia with cerebral gyral simplification".Am. J. Hum. Genet.77(3): 477–83.doi:10.1086/444400.PMC1226212.PMID16080122.
  21. ^Online Mendelian Inheritance in Man(OMIM):Cerebellar Hypoplasia, VLDLR-Associated; VLDLRCH - 224050
  22. ^Boycott KM, Parboosingh JS (2008)."VLDLR-Associated Cerebellar Hypoplasia".In Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP (eds.).GeneReviews [Internet].University of Washington, Seattle.PMID20301729.
  23. ^abPennings M, Meurs I, Ye D, Out R, Hoekstra M, Van Berkel TJ, Van Eck M (October 2006)."Regulation of cholesterol homeostasis in macrophages and consequences for atherosclerotic lesion development".FEBS Lett.580(23): 5588–96.doi:10.1016/j.febslet.2006.08.022.PMID16935283.S2CID42158329.

Further reading

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