LDL-receptor-related protein-associated protein

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LRPAP1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesLRPAP1, A2MRAP, A2RAP, HBP44, MRAP, MYP23, RAP, alpha-2-MRAP, LDL-receptor-related protein associated protein, LDL receptor related protein associated protein 1
External IDsOMIM: 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 MbChr 5: 35.25 – 35.26 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Alpha-2-MRAP_N
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
PfamPF06400
InterProIPR009066
SCOP21lre / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
Alpha-2-MRAP_C
solution structure of domain 3 of rap
Identifiers
SymbolAlpha-2-MRAP_C
PfamPF06401
InterProIPR010483
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure 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]

Mutations and diseases related to LRPAP1

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]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000163956 – Ensembl, May 2017
  2. ^ a b c 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. ^ a b c d e f g 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. ^ a b 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. ^ a b c d 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

External links

This article incorporates text from the public domain Pfam and InterPro: IPR010483
Retrieved from "https://mdwiki.org/wiki/LDL-receptor-related_protein-associated_protein"