LDL-receptor-related protein-associated protein

Last updated
LRPAP1
Protein LRPAP1 PDB 1lre.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases LRPAP1 , A2MRAP, A2RAP, HBP44, MRAP, MYP23, RAP, alpha-2-MRAP, LDL-receptor-related protein associated protein, LDL receptor related protein associated protein 1
External IDs OMIM: 104225 MGI: 96829 HomoloGene: 37612 GeneCards: LRPAP1
Orthologs
SpeciesHumanMouse
Entrez

4043

16976

Ensembl

ENSG00000163956

ENSMUSG00000029103

UniProt

P30533

P55302

RefSeq (mRNA)

NM_002337

NM_013587

RefSeq (protein)

NP_002328

NP_038615

Location (UCSC) Chr 4: 3.5 – 3.53 Mb Chr 5: 35.25 – 35.26 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
Alpha-2-MRAP_N
PDB 2fyl EBI.jpg
haddock model of the complex between double module of lrp, cr56, and first domain of receptor associated protein, rap-d1.
Identifiers
SymbolAlpha-2-MRAP_N
Pfam PF06400
InterPro IPR009066
SCOP2 1lre / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
Alpha-2-MRAP_C
PDB 2ftu EBI.jpg
solution structure of domain 3 of rap
Identifiers
SymbolAlpha-2-MRAP_C
Pfam PF06401
InterPro IPR010483
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Low density lipoprotein receptor-related protein-associated protein 1 also known as LRPAP1 or RAP is a chaperone protein which in humans is encoded by the LRPAP1 gene. [5] [6]

Function

LRPAP1 is involved with trafficking of certain members of the LDL receptor family including LRP1 and LRP2. [7] It is a glycoprotein that binds to the alpha-2-macroglobulin receptor, as well as to other members of the low density lipoprotein receptor family. It acts to inhibit the binding of all known ligands for these receptors, and may prevent receptor aggregation and degradation in the endoplasmic reticulum, thereby acting as a molecular chaperone. [8] It may be under the regulatory control of calmodulin, since it is able to bind calmodulin and be phosphorylated by calmodulin-dependent kinase II.

Interactions

LDL-receptor-related protein-associated protein has been shown to interact with LRP2. [9] [10]

Lipid metabolizing proteins may elevate susceptibility to dementia leading to differences in genetic makeup. [11] PCR-restriction fragment length polymorphism technique is used for genotyping of LRPAP1 intron 5 insertion/deletion. [11] The studies suggested that DD genotype and *D allele of LRPAP gene showed increased frequency for degenerative dementias on comparison with the control group and that LRPAP1-D allele remarkably increases the vulnerability to degenerative dementias. [11] On genotyping of LRPAP1 polymorphism is observed because of 37 base pair insertion in intron 5. [11] Also insertion allele being larger than deletion allele makes possible in detecting difference by gel electrophoresis. [12] Suppression of receptor-binding domain of LRP LDLR is due to overexpression of LRPAP (the protein product of LRPAP gene). [13] LRP gives protection across LDL by LRPAP and its downregulation may be subjected for an elevation of LDL and Ab-related neuronal toxicity as LRP supports in binding of ligand and internalization of LRP ligands like apo-E-enriched LDL cholesterol and Ab protein. [11] Insertion/deletion is an intronic polymorphism of LRPAP gene, Influencing DD genotype and D allele for the synthesis of LRPAP protein can be lrp-mediated mechanism contributing to dementia. [11] Concern for developing sensitivity for dementia is because of several shared common genetic platforms and DD genotype or D allele of LRPAP gene may be one such. [11] So on 37-bp insertion/deletion that was studied as an intronic polymorphism, it could be having an unintended pursuit for lipid receptor protein by regulation of LRPAP expression, or it could be in linkage disequilibrium in addition to other biologically relevant polymorphism in the LRPAP1 or an adjacent gene in chromosome 4. [14] Results being consistent with earlier study where the authors have endowed deletion allele frequency clearly high in late-onset Alzheimer’s disease patients on comparison with non-demented aged controls. [14]

Mendelian forms of myopia has been identified in four consanguineous families and are the likely causal mutations implementing exome /autozygome investigated to recognize homozygous truncating variants in LRPAP1. [15] Influencing TGF-β activity, chaperone of LRP1 is encoded by LRPAP1.Notably salient deficiency of LRP1 and upregulation of TGF-β in affected individuals cells, the known data being consistent on the importance of TGF-β in remodeling for the sclera of myopia and the increased frequency in individuals for myopia having Marfan syndrome which has characteristics of upregulated TGF-β signaling. [16] Analysizing the absence of the normal protein was done with immunoblot for affected individuals having LRPAP1 mutations revealing the mutations in LRPAP1 probability of loss-of-function mutations. [15] Encoding (Low Density Lipoprotein Receptor-Related Protein Associated protein 1) LRPAP is a largely expressed gene, and a 357 amino acid protein thought as a chaperone binding and protecting the lipoproteins receptor-related proteins LRP1 and LRP2. [17] [18] A model suggested by a study wherein LRPAP1 leading to deficiency of LRP1 which was responsible to perturbation of TGF-β regulation and might cause abnormal ECM remodeling in the eye development. [15] On observation for increasing axial length was one of the salient features of Marfan syndrome also resulting in TGF-β supported the model. [19] [20] Therefore, individuals having myopia responding to therapeutic strategy initiated before ECM remodeling could be considered as an approach for individuals with LRPAP1 related myopia. [15]

Related Research Articles

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Lipoprotein lipase (LPL) (EC 3.1.1.34, systematic name triacylglycerol acylhydrolase (lipoprotein-dependent)) is a member of the lipase gene family, which includes pancreatic lipase, hepatic lipase, and endothelial lipase. It is a water-soluble enzyme that hydrolyzes triglycerides in lipoproteins, such as those found in chylomicrons and very low-density lipoproteins (VLDL), into two free fatty acids and one monoacylglycerol molecule:

<span class="mw-page-title-main">LDL receptor</span> Mammalian protein found in Homo sapiens

The low-density lipoprotein receptor (LDL-R) is a mosaic protein of 839 amino acids that mediates the endocytosis of cholesterol-rich low-density lipoprotein (LDL). It is a cell-surface receptor that recognizes apolipoprotein B100 (ApoB100), which is embedded in the outer phospholipid layer of very low-density lipoprotein (VLDL), their remnants—i.e. intermediate-density lipoprotein (IDL), and LDL particles. The receptor also recognizes apolipoprotein E (ApoE) which is found in chylomicron remnants and IDL. In humans, the LDL receptor protein is encoded by the LDLR gene on chromosome 19. It belongs to the low density lipoprotein receptor gene family. It is most significantly expressed in bronchial epithelial cells and adrenal gland and cortex tissue.

<span class="mw-page-title-main">Apolipoprotein E</span> Cholesterol-transporting protein most notably implicated in Alzheimers disease

Apolipoprotein E (Apo-E) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular diseases. It is encoded in humans by the gene APOE.

<span class="mw-page-title-main">Apolipoprotein B</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Low-density lipoprotein receptor gene family</span>

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<span class="mw-page-title-main">Thrombospondin 1</span> Protein-coding gene in the species Homo sapiens

Thrombospondin 1, abbreviated as THBS1, is a protein that in humans is encoded by the THBS1 gene.

<span class="mw-page-title-main">Low-density lipoprotein receptor-related protein 8</span> Cell surface receptor, part of the low-density lipoprotein receptor family

Low-density lipoprotein receptor-related protein 8 (LRP8), also known as apolipoprotein E receptor 2 (ApoER2), is a protein that in humans 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 is associated with certain neurological diseases.

<span class="mw-page-title-main">Hepatic lipase</span> Mammalian protein found in Homo sapiens

Hepatic lipase (HL), also called hepatic triglyceride lipase (HTGL) or LIPC (for "lipase, hepatic"), is a form of lipase, catalyzing the hydrolysis of triacylglyceride. Hepatic lipase is coded by chromosome 15 and its gene is also often referred to as HTGL or LIPC. Hepatic lipase is expressed mainly in liver cells, known as hepatocytes, and endothelial cells of the liver. The hepatic lipase can either remain attached to the liver or can unbind from the liver endothelial cells and is free to enter the body's circulation system. When bound on the endothelial cells of the liver, it is often found bound to heparan sulfate proteoglycans (HSPG), keeping HL inactive and unable to bind to HDL (high-density lipoprotein) or IDL (intermediate-density lipoprotein). When it is free in the bloodstream, however, it is found associated with HDL to maintain it inactive. This is because the triacylglycerides in HDL serve as a substrate, but the lipoprotein contains proteins around the triacylglycerides that can prevent the triacylglycerides from being broken down by HL.

<span class="mw-page-title-main">ACVRL1</span> Protein-coding gene in humans

Serine/threonine-protein kinase receptor R3 is an enzyme that in humans is encoded by the ACVRL1 gene.

<span class="mw-page-title-main">LRP2</span> Mammalian protein found in Homo sapiens

Low density lipoprotein receptor-related protein 2 also known as LRP-2 or megalin is a protein which in humans is encoded by the LRP2 gene.

<span class="mw-page-title-main">LRP1</span> Mammalian protein found in Homo sapiens

Low density lipoprotein receptor-related protein 1 (LRP1), also known as alpha-2-macroglobulin receptor (A2MR), apolipoprotein E receptor (APOER) or cluster of differentiation 91 (CD91), is a protein forming a receptor found in the plasma membrane of cells involved in receptor-mediated endocytosis. In humans, the LRP1 protein is encoded by the LRP1 gene. LRP1 is also a key signalling protein and, thus, involved in various biological processes, such as lipoprotein metabolism and cell motility, and diseases, such as neurodegenerative diseases, atherosclerosis, and cancer.

<span class="mw-page-title-main">LRP5</span> Protein-coding gene in the species Homo sapiens

Low-density lipoprotein receptor-related protein 5 is a protein that in humans is encoded by the LRP5 gene. LRP5 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway. Mutations in LRP5 can lead to considerable changes in bone mass. A loss-of-function mutation causes osteoporosis pseudoglioma syndrome with a decrease in bone mass, while a gain-of-function mutation causes drastic increases in bone mass.

<span class="mw-page-title-main">LRP6</span> Protein-coding gene in the species Homo sapiens

Low-density lipoprotein receptor-related protein 6 is a protein that in humans is encoded by the LRP6 gene. LRP6 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway.

<span class="mw-page-title-main">Low-density lipoprotein receptor adapter protein 1</span> Protein-coding gene in the species Homo sapiens

Low-density lipoprotein receptor adapter protein 1 is a protein that in humans is encoded by the LDLRAP1 gene.

<span class="mw-page-title-main">Pregnancy zone protein</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">LRP1B</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">SYNJ2BP</span> Protein-coding gene in the species Homo sapiens

Synaptojanin-2-binding protein is a protein that in humans is encoded by the SYNJ2BP gene.

Lipoprotein receptor-related proteins, low density lipoprotein receptor-related proteins (HGNC) or prolow-density lipoprotein receptor-related protein (UniProt), abbreviated LRP, are a group of proteins.

<span class="mw-page-title-main">LRP3</span> Protein-coding gene in the species Homo sapiens

Low density lipoprotein receptor-related protein 3 (LRP-3) is a protein that in humans is encoded by the LRP3 gene.

<span class="mw-page-title-main">A2ML1</span> Protein-coding gene in humans

Alpha-2-macroglobulin-like 1 abbreviated as α2ML1 is a protein that in humans is encoded by the A2ML1 gene. α2ML1 is a large, 180 kDa protein found in the epidermis. It is able to the inhibit the chymotryptic activity of KLK7.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000163956 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000029103 - 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. ↑ Strickland DK, Ashcom JD, Williams S, Battey F, Behre E, McTigue K, Battey JF, Argraves WS (Jul 1991). "Primary structure of alpha 2-macroglobulin receptor-associated protein. Human homologue of a Heymann nephritis antigen". The Journal of Biological Chemistry. 266 (20): 13364–9. doi: 10.1016/S0021-9258(18)98848-4 . PMID   1712782.
  6. ↑ Korenberg JR, Argraves KM, Chen XN, Tran H, Strickland DK, Argraves WS (Jul 1994). "Chromosomal localization of human genes for the LDL receptor family member glycoprotein 330 (LRP2) and its associated protein RAP (LRPAP1)". Genomics. 22 (1): 88–93. doi:10.1006/geno.1994.1348. PMID   7959795.
  7. ↑ "Entrez Gene: LRPAP1 low density lipoprotein receptor-related protein associated protein 1".
  8. ↑ Nielsen PR, Ellgaard L, Etzerodt M, Thogersen HC, Poulsen FM (Jul 1997). "The solution structure of the N-terminal domain of alpha2-macroglobulin receptor-associated protein". Proceedings of the National Academy of Sciences of the United States of America. 94 (14): 7521–5. Bibcode:1997PNAS...94.7521N. doi: 10.1073/pnas.94.14.7521 . PMC   23854 . PMID   9207124.
  9. ↑ Lou X, McQuistan T, Orlando RA, Farquhar MG (Apr 2002). "GAIP, GIPC and Galphai3 are concentrated in endocytic compartments of proximal tubule cells: putative role in regulating megalin's function". Journal of the American Society of Nephrology. 13 (4): 918–27. doi: 10.1681/ASN.V134918 . PMID   11912251.
  10. ↑ Orlando RA, Farquhar MG (Apr 1994). "Functional domains of the receptor-associated protein (RAP)". Proceedings of the National Academy of Sciences of the United States of America. 91 (8): 3161–5. Bibcode:1994PNAS...91.3161O. doi: 10.1073/pnas.91.8.3161 . PMC   43535 . PMID   7512726.
  11. 1 2 3 4 5 6 7 Pandey P, Pradhan S, Mittal B (2008). "LRP-associated protein gene (LRPAP1) and susceptibility to degenerative dementia". Genes, Brain and Behavior. 7 (8): 943–950. doi: 10.1111/j.1601-183X.2008.00436.x . PMID   18721259. S2CID   19207648.
  12. ↑ Pandey P, Pradhan S, Mittal B (2008). "LRP-associated protein gene (LRPAP1) and susceptibility to degenerative dementia". Genes, Brain and Behavior. 7 (8): 943–50. doi: 10.1111/j.1601-183X.2008.00436.x . PMID   18721259. S2CID   19207648.
  13. ↑ Willnow TE, Sheng Z, Ishibashi S, Herz J (1994). "Inhibition of hepatic chylomicron remnant uptake by gene transfer of a receptor antagonist". Science. 264 (5164): 1471–4. Bibcode:1994Sci...264.1471W. doi:10.1126/science.7515194. PMID   7515194.
  14. 1 2 Sánchez L, Alvarez V, González P, González I, Alvarez R, Coto E (2001). "Variation in the LRP-associated protein gene (LRPAP1) is associated with late-onset Alzheimer disease". American Journal of Medical Genetics. 105 (1): 76–8. doi:10.1002/1096-8628(20010108)105:1<76::aid-ajmg1066>3.3.co;2-i. PMID   11425005.
  15. 1 2 3 4 Aldahmesh MA, Khan AO, Alkuraya H, Adly N, Anazi S, Al-Saleh AA, Mohamed JY, Hijazi H, Prabakaran S, Tacke M, Al-Khrashi A, Hashem M, Reinheckel T, Assiri A, Alkuraya FS (2013-08-08). "Mutations in LRPAP1 Are Associated with Severe Myopia in Humans". Am J Hum Genet. 93 (2): 313–20. doi:10.1016/j.ajhg.2013.06.002. PMC   3738831 . PMID   23830514.
  16. ↑ Aldahmesh MA, Khan AO, Alkuraya H, Adly N, Anazi S, Al-Saleh AA, Mohamed JY, Hijazi H, Prabakaran S, Tacke M, Al-Khrashi A, Hashem M, Reinheckel T, Assiri A, Alkuraya FS (2013). "Mutations in LRPAP1 are associated with severe myopia in humans". American Journal of Human Genetics. 93 (2): 313–20. doi:10.1016/j.ajhg.2013.06.002. PMC   3738831 . PMID   23830514.
  17. ↑ Willnow TE, Armstrong SA, Hammer RE, Herz J (1995). "Functional expression of low density lipoprotein receptor-related protein is controlled by receptor-associated protein in vivo". Proceedings of the National Academy of Sciences of the United States of America. 92 (10): 4537–41. Bibcode:1995PNAS...92.4537W. doi: 10.1073/pnas.92.10.4537 . PMC   41979 . PMID   7538675.
  18. ↑ Willnow TE, Rohlmann A, Horton J, Otani H, Braun JR, Hammer RE, Herz J (1996). "RAP, a specialized chaperone, prevents ligand-induced ER retention and degradation of LDL receptor-related endocytic receptors". The EMBO Journal. 15 (11): 2632–9. doi:10.1002/j.1460-2075.1996.tb00623.x. PMC   450198 . PMID   8654360.
  19. ↑ Loeys BL, Dietz HC, Braverman AC, Callewaert BL, De Backer J, Devereux RB, Hilhorst-Hofstee Y, Jondeau G, Faivre L, Milewicz DM, Pyeritz RE, Sponseller PD, Wordsworth P, De Paepe AM (2010). "The revised Ghent nosology for the Marfan syndrome". Journal of Medical Genetics. 47 (7): 476–85. doi:10.1136/jmg.2009.072785. hdl: 1854/LU-1013955 . PMID   20591885. S2CID   13895128.
  20. ↑ Brooke BS, Habashi JP, Judge DP, Patel N, Loeys B, Dietz HC (2008). "Angiotensin II blockade and aortic-root dilation in Marfan's syndrome". The New England Journal of Medicine. 358 (26): 2787–95. doi:10.1056/NEJMoa0706585. PMC   2692965 . PMID   18579813.

Further reading

This article incorporates text from the public domain Pfam and InterPro: IPR010483
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