LRP2

Low density lipoprotein-related protein 2 also known as LRP2 or megalin is a protein which in humans is encoded by the LRP2 gene.[5][6][7]

LRP2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2M0P
Identifiers
Aliases	LRP2, DBS, GP330, LDL receptor related protein 2, LRP-2
External IDs	OMIM: 600073 MGI: 95794 HomoloGene: 20952 GeneCards: LRP2
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2q31.1 Start 169,127,109 bp[1] End 169,362,534 bp[1]
Gene location (Mouse) Chr. Chromosome 2 (mouse)[2] Band 2 C2|2 40.74 cM Start 69,424,340 bp[2] End 69,586,065 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • calcium ion binding • SH3 domain binding • metal ion binding • GO:0001948 protein binding • low-density lipoprotein receptor activity • drug binding • steroid hormone receptor binding • chaperone binding Cellular component • integral component of membrane • endosome • Golgi apparatus • membrane • receptor complex • cell membrane • endocytic vesicle • apical part of cell • brush border membrane • lysosomal membrane • apical plasma membrane • endoplasmic reticulum • brush border • clathrin-coated pit • lysosome • extracellular exosome • clathrin-coated vesicle membrane • external side of plasma membrane • axon • dendrite • endosome lumen • cell projection Biological process • endocytosis • ventricular septum development • vitamin D metabolic process • lipid metabolism • receptor-mediated endocytosis • coronary vasculature development • retinoid metabolic process • aorta development • heart development • forebrain development • cellular proliferation • vitamin metabolic process • lipoprotein transport • membrane organization • neural tube closure • secondary heart field specification • outflow tract septum morphogenesis • ventricular compact myocardium morphogenesis • nervous system development • sensory perception of sound • male gonad development • metal ion transport • negative regulation of BMP signaling pathway • positive regulation of neurogenesis • vagina development • coronary artery morphogenesis • pulmonary artery morphogenesis • positive regulation of oligodendrocyte progenitor proliferation • neuron projection arborization • folic acid import across plasma membrane • positive regulation of lysosomal protein catabolic process Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	4036	14725
Ensembl	ENSG00000081479	ENSMUSG00000027070
UniProt	P98164	A2ARV4
RefSeq (mRNA)	NM_004525	NM_001081088
RefSeq (protein)	NP_004516	NP_001074557
Location (UCSC)	Chr 2: 169.13 – 169.36 Mb	Chr 2: 69.42 – 69.59 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

LRP2 was identified as the antigen of rat experimental membranous nephropathy (Heyman nephritis) and originally named gp330 and subsequently megalin[8] and later LRP2. LRP2/megalin is a multiligand binding receptor found in the plasma membrane of many absorptive epithelial cells. LRP2/megalin is a member of a family of receptors with structural similarities to the low density lipoprotein receptor (LDLR). LRP2/megalin functions to mediate endocytosis of ligands leading to degradation in lysosomes or transcytosis. LRP2/megalin can also form complexes with cubilin: those complexes are able to reabsorb several molecules and can be inhibited by sodium maleate. LRP2 is expressed in epithelial cells of the thyroid (thyrocytes), where it can serve as a receptor for the protein thyroglobulin (Tg).[9]

Clinical significance

Mutations in the LRP2 gene are associated with Donnai-Barrow syndrome.[10]

Interactions

LRP2 has been shown to interact with:

• DAB2,[11]
• DLG4,[12][13]
• GIPC1,[12][14][15]
• ITGB1BP1,[12]
• LDL-receptor-related protein associated protein,[14][16]
• LDLRAP1,[17]
• MAGI1,[18]
• MAPK8IP1,[12][15]
• MAPK8IP2,[12][15]
• NOS1AP,[12] and
• SYNJ2BP.[12]

References

1. GRCh38: Ensembl release 89: ENSG00000081479 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000027070 - 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. "Entrez Gene: LRP2 low density lipoprotein-related protein 2".
6. Korenberg JR, Argraves KM, Chen XN, Tran H, Strickland DK, Argraves WS (July 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. Farquhar MG (September 1995). "The unfolding story of megalin (gp330): now recognized as a drug receptor". J. Clin. Invest. 96 (3): 1184. doi:10.1172/JCI118149. PMC 185736. PMID 7657789.
8. Farquhar MG, Saito A, Kerjaschki D, Orlando RA (July 1995). "The Heymann nephritis antigenic complex: megalin (gp330) and RAP". J. Am. Soc. Nephrol. 6 (1): 35–47. PMID 7579068.
9. Zheng G, Marino' M, Zhao J, McCluskey RT (March 1998). "Megalin (gp330): a putative endocytic receptor for thyroglobulin (Tg)". Endocrinology. 139 (3): 1462–5. doi:10.1210/en.139.3.1462. PMID 9492085.
10. Kantarci S, Al-Gazali L, Hill RS, Donnai D, Black GC, Bieth E, Chassaing N, Lacombe D, Devriendt K, Teebi A, Loscertales M, Robson C, Liu T, MacLaughlin DT, Noonan KM, Russell MK, Walsh CA, Donahoe PK, Pober BR (August 2007). "Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes". Nat. Genet. 39 (8): 957–9. doi:10.1038/ng2063. PMC 2891728. PMID 17632512.
11. Oleinikov AV, Zhao J, Makker SP (May 2000). "Cytosolic adaptor protein Dab2 is an intracellular ligand of endocytic receptor gp600/megalin". Biochem. J. 347 (3): 613–21. doi:10.1042/0264-6021:3470613. PMC 1220996. PMID 10769163.
12. Gotthardt M, Trommsdorff M, Nevitt MF, Shelton J, Richardson JA, Stockinger W, Nimpf J, Herz J (August 2000). "Interactions of the low density lipoprotein receptor gene family with cytosolic adaptor and scaffold proteins suggest diverse biological functions in cellular communication and signal transduction". J. Biol. Chem. 275 (33): 25616–24. doi:10.1074/jbc.M000955200. PMID 10827173.
13. Larsson M, Hjälm G, Sakwe AM, Engström A, Höglund AS, Larsson E, Robinson RC, Sundberg C, Rask L (July 2003). "Selective interaction of megalin with postsynaptic density-95 (PSD-95)-like membrane-associated guanylate kinase (MAGUK) proteins". Biochem. J. 373 (Pt 2): 381–91. doi:10.1042/BJ20021958. PMC 1223512. PMID 12713445.
14. Lou X, McQuistan T, Orlando RA, Farquhar MG (April 2002). "GAIP, GIPC and Galphai3 are concentrated in endocytic compartments of proximal tubule cells: putative role in regulating megalin's function". J. Am. Soc. Nephrol. 13 (4): 918–27. PMID 11912251.
15. Petersen HH, Hilpert J, Militz D, Zandler V, Jacobsen C, Roebroek AJ, Willnow TE (February 2003). "Functional interaction of megalin with the megalinbinding protein (MegBP), a novel tetratrico peptide repeat-containing adaptor molecule". J. Cell Sci. 116 (Pt 3): 453–61. doi:10.1242/jcs.00243. PMID 12508107.
16. Orlando RA, Farquhar MG (April 1994). "Functional domains of the receptor-associated protein (RAP)". Proc. Natl. Acad. Sci. U.S.A. 91 (8): 3161–5. doi:10.1073/pnas.91.8.3161. PMC 43535. PMID 7512726.
17. Nagai M, Meerloo T, Takeda T, Farquhar MG (December 2003). "The adaptor protein ARH escorts megalin to and through endosomes". Mol. Biol. Cell. 14 (12): 4984–96. doi:10.1091/mbc.E03-06-0385. PMC 284800. PMID 14528014.
18. Patrie KM, Drescher AJ, Goyal M, Wiggins RC, Margolis B (April 2001). "The membrane-associated guanylate kinase protein MAGI-1 binds megalin and is present in glomerular podocytes". J. Am. Soc. Nephrol. 12 (4): 667–77. PMID 11274227.

Further reading

• Farquhar MG, Saito A, Kerjaschki D, Orlando RA (1995). "The Heymann nephritis antigenic complex: megalin (gp330) and RAP". J. Am. Soc. Nephrol. 6 (1): 35–47. PMID 7579068.
• Farquhar MG (1995). "The unfolding story of megalin (gp330): now recognized as a drug receptor". J. Clin. Invest. 96 (3): 1184. doi:10.1172/JCI118149. PMC 185736. PMID 7657789.
• Christensen EI, Birn H (2002). "Megalin and cubilin: multifunctional endocytic receptors". Nat. Rev. Mol. Cell Biol. 3 (4): 256–66. doi:10.1038/nrm778. PMID 11994745.
• Saito A, Takeda T, Hama H, Oyama Y, Hosaka K, Tanuma A, Kaseda R, Ueno M, Nishi S, Ogasawara S, Gondaira F, Suzuki Y, Gejyo F (2006). "Role of megalin, a proximal tubular endocytic receptor, in the pathogenesis of diabetic and metabolic syndrome-related nephropathies: protein metabolic overload hypothesis". Nephrology (Carlton, Vic.). 10 Suppl: S26–31. doi:10.1111/j.1440-1797.2005.00453.x. PMID 16174284.
• Fisher CE, Howie SE (2006). "The role of megalin (LRP-2/Gp330) during development". Dev. Biol. 296 (2): 279–97. doi:10.1016/j.ydbio.2006.06.007. PMID 16828734.
• Christensen EI, Gliemann J, Moestrup SK (1992). "Renal tubule gp330 is a calcium binding receptor for endocytic uptake of protein". J. Histochem. Cytochem. 40 (10): 1481–90. doi:10.1177/40.10.1382088. PMID 1382088.
• Raychowdhury R, Niles JL, McCluskey RT, Smith JA (1989). "Autoimmune target in Heymann nephritis is a glycoprotein with homology to the LDL receptor". Science. 244 (4909): 1163–5. doi:10.1126/science.2786251. PMID 2786251.
• Orlando RA, Farquhar MG (1994). "Functional domains of the receptor-associated protein (RAP)". Proc. Natl. Acad. Sci. U.S.A. 91 (8): 3161–5. doi:10.1073/pnas.91.8.3161. PMC 43535. PMID 7512726.
• Kounnas MZ, Chappell DA, Strickland DK, Argraves WS (1993). "Glycoprotein 330, a member of the low density lipoprotein receptor family, binds lipoprotein lipase in vitro". J. Biol. Chem. 268 (19): 14176–81. PMID 7686151.
• Kounnas MZ, Loukinova EB, Stefansson S, Harmony JA, Brewer BH, Strickland DK, Argraves WS (1995). "Identification of glycoprotein 330 as an endocytic receptor for apolipoprotein J/clusterin". J. Biol. Chem. 270 (22): 13070–5. doi:10.1074/jbc.270.22.13070. PMID 7768901.
• Korenberg JR, Argraves KM, Chen XN, Tran H, Strickland DK, Argraves WS (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.
• Lundgren S, Hjälm G, Hellman P, Ek B, Juhlin C, Rastad J, Klareskog L, Akerström G, Rask L (1994). "A protein involved in calcium sensing of the human parathyroid and placental cytotrophoblast cells belongs to the LDL-receptor protein superfamily". Exp. Cell Res. 212 (2): 344–50. doi:10.1006/excr.1994.1153. PMID 8187828.
• Moestrup SK, Nielsen S, Andreasen P, Jørgensen KE, Nykjaer A, Røigaard H, Gliemann J, Christensen EI (1993). "Epithelial glycoprotein-330 mediates endocytosis of plasminogen activator-plasminogen activator inhibitor type-1 complexes". J. Biol. Chem. 268 (22): 16564–70. PMID 8344937.
• Hjälm G, Murray E, Crumley G, Harazim W, Lundgren S, Onyango I, Ek B, Larsson M, Juhlin C, Hellman P, Davis H, Akerström G, Rask L, Morse B (1996). "Cloning and sequencing of human gp330, a Ca(2+)-binding receptor with potential intracellular signaling properties". Eur. J. Biochem. 239 (1): 132–7. doi:10.1111/j.1432-1033.1996.0132u.x. PMID 8706697.
• Willnow TE, Hilpert J, Armstrong SA, Rohlmann A, Hammer RE, Burns DK, Herz J (1996). "Defective forebrain development in mice lacking gp330/megalin". Proc. Natl. Acad. Sci. U.S.A. 93 (16): 8460–4. doi:10.1073/pnas.93.16.8460. PMC 38693. PMID 8710893.
• Cui S, Verroust PJ, Moestrup SK, Christensen EI (1996). "Megalin/gp330 mediates uptake of albumin in renal proximal tubule". Am. J. Physiol. 271 (4 Pt 2): F900–7. doi:10.1152/ajprenal.1996.271.4.F900. PMID 8898021.
• Lundgren S, Carling T, Hjälm G, Juhlin C, Rastad J, Pihlgren U, Rask L, Akerström G, Hellman P (1997). "Tissue distribution of human gp330/megalin, a putative Ca(2+)-sensing protein". J. Histochem. Cytochem. 45 (3): 383–92. doi:10.1177/002215549704500306. PMID 9071320.
• Birn H, Verroust PJ, Nexo E, Hager H, Jacobsen C, Christensen EI, Moestrup SK (1997). "Characterization of an epithelial approximately 460-kDa protein that facilitates endocytosis of intrinsic factor-vitamin B12 and binds receptor-associated protein". J. Biol. Chem. 272 (42): 26497–504. doi:10.1074/jbc.272.42.26497. PMID 9334227.

External links

• GeneReviews/NCBI/NIH/UW entry on Donnai-Barrow Syndrome