LRP2
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.[5][6][7]
Function
LRP2 was identified as the antigen of rat experimental membranous nephropathy (Heyman nephritis) and originally named gp330 and subsequently megalin
LRP2 is expressed in epithelial cells of the thyroid (thyrocytes), where it can serve as a receptor for the protein thyroglobulin (Tg).[12] LRP2 is also expressed on the apical surface of epithelial cells in the proximal tubule of the kidney.[9] It is highly expressed in the first segment (S1) of the proximal tubule, with decreasing expression in the second (S2) and third segment (S3) of the proximal tubule.[9] LRP2 is also expressed in podocytes, and antigenic response to LRP2 in podocytes is the primary cause of Heymann nephritis in rats.[8]
LRP2/megalin functions to mediate endocytosis of ligands leading to degradation in lysosomes or transcytosis. LRP2/megalin can also form complexes with CUBAM, the cubilin and amnionless complex. Those complexes are able to reabsorb several molecules and can be inhibited by sodium maleate. LRP2 and CUBAM are responsible for the uptake of most of the filtered proteins that escape the glomerular filtration barrier in the proximal tubule of the kidney.[13][14] The endocytic capacity of the proximal tubule cells is dictated by the combined function of LRP2, CUBAM, and Dab2.[14]
The epithelial cells of the proximal tubule are highly polarized and have a robust apical endocytic pathway, subapical compartmentalization, and large endocytic capacity.[13] This pathway is mediated by LRP2 and CUBAM, where Dab2 binds to the cytoplasmic tails of both LRP2 and CUBAM to initiate clathrin-coated endocytosis.[9][13] Once internalized, the endosomes release their clathrin coats and fuse with a dense subapical network of tubules to recycle receptors back to the apical surface.[9] As the endosomes acidify, LRP2 release its cargo and undergoes a conformational change which collapses the binding pockets to inhibit ligands rebinding to LRP2 in the endosomes.[11] Recycling of the LRP2 occurs from apical vacuoles with Rab11a positive endosomes, also referred to as dense apical tubules.[15] The vesicles are directed back to the plasma membrane where LRP2 undergoes another conformational change due to the change in pH and becomes active again.[11][15] According to LRP2/megalin kinetic modeling, the rate of megalin recycling and return to the apical surface from dense apical tubules has the largest impact on determining the overall endocytic capacity of proximal tubule cells and the endocytic rate of LRP2.[15] The fraction of LRP2 at the apical surface is important for the continued ability of the protein to reabsorb filtered proteins in the proximal tubule to maintain the robust endocytic capacity of these cells.[9][13][14]
Clinical significance
Disfunction in the LRP2-mediated endocytic trafficking and endocytic capacity in the proximal tubule can result in low molecular weight proteinuria, which is a hallmark of many diseases.[13]
Mutations in the LRP2 gene are associated with
Dent's Disease (Dent 1) is associated with a drop in LRP2/megalin protein level in the proximal tubule with no detectable decrease in mRNA, suggesting that the loss of ClC-5, the gene mutated in Dent's Disease, shortens the half-life of the LRP2 receptor.[17][18] The loss of ClC-5 has been found to delay the early endosome maturation in the LRP2 trafficking in the proximal tubule cells.[18]
LRP2 has been shown to play a role in the development of nephrotoxic acute kidney injury (AKI) by mediating the uptake of nephrotoxic agents.[19] However, there have been no further studies to show the functional importance of LRP2 or CUBAM in the progression of AKI.
A decrease in LRP2 receptor expression has been reported in animal models of acute and chronic kidney diseases.[19]
Interactions
LRP2 has been shown to associate with the following proteins in the plasma membrane/cytosol of cells:
- CUBAM,[9][13]
- DAB2,[20]
- DLG4,[21][22]
- GIPC1,[21][23][24]
- ITGB1BP1,[21]
- LDLRAP1,[26]
- MAGI1,[27]
- MAPK8IP1,[21][24]
- MAPK8IP2,[21][24]
- NOS1AP,[21] and
- SYNJ2BP.[21]
LRP2 has been shown to bind to the following ligands:
- Albumin[9]
- Vitamin D-binding protein[9]
- Hemoglobin[9]
- Myoglobin[9]
- Angiotensin II[9]
- Insulin[9]
- Leptin[9]
- Prolactin[9]
- Epidermal Growth Factor[9]
- Cathepsin B[9]
- Immunoglobulin light chains[9]
- Ca2+[9]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000081479 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000027070 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: LRP2 low density lipoprotein-related protein 2".
- PMID 7959795.
- PMID 7657789.
- ^ PMID 7579068.
- ^ PMID 27813828.
- PMID 15134832.
- ^ PMID 36750096.
- PMID 9492085.
- ^ PMID 34036593.
- ^ PMID 34747197.
- ^ PMID 36325513.
- PMID 17632512.
- PMID 33015630.
- ^ S2CID 256737627.
- ^ PMID 26759048.
- PMID 10769163.
- ^ PMID 10827173.
- PMID 12713445.
- ^ PMID 11912251.
- ^ PMID 12508107.
- PMID 7512726.
- PMID 14528014.
- PMID 11274227.
Further reading
- Longoni M, Kantarci S, Donnai D, Pober BR (August 2008). "Donnai-Barrow Syndrome". In Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, Gripp KW, et al. (eds.). GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle. PMID 20301732.
- Farquhar MG, Saito A, Kerjaschki D, Orlando RA (July 1995). "The Heymann nephritis antigenic complex: megalin (gp330) and RAP". Journal of the American Society of Nephrology. 6 (1): 35–47. PMID 7579068.
- Farquhar MG (September 1995). "The unfolding story of megalin (gp330): now recognized as a drug receptor". The Journal of Clinical Investigation. 96 (3): 1184. PMID 7657789.
- Christensen EI, Birn H (April 2002). "Megalin and cubilin: multifunctional endocytic receptors". Nature Reviews. Molecular Cell Biology. 3 (4): 256–266. S2CID 21893726.
- Saito A, Takeda T, Hama H, Oyama Y, Hosaka K, Tanuma A, et al. (October 2005). "Role of megalin, a proximal tubular endocytic receptor, in the pathogenesis of diabetic and metabolic syndrome-related nephropathies: protein metabolic overload hypothesis". Nephrology. 10 (Suppl): S26–S31. S2CID 42737684.
- Fisher CE, Howie SE (August 2006). "The role of megalin (LRP-2/Gp330) during development". Developmental Biology. 296 (2): 279–297. PMID 16828734.
- Christensen EI, Gliemann J, Moestrup SK (October 1992). "Renal tubule gp330 is a calcium binding receptor for endocytic uptake of protein". The Journal of Histochemistry and Cytochemistry. 40 (10): 1481–1490. S2CID 24323611.
- Raychowdhury R, Niles JL, McCluskey RT, Smith JA (June 1989). "Autoimmune target in Heymann nephritis is a glycoprotein with homology to the LDL receptor". Science. 244 (4909): 1163–1165. PMID 2786251.
- Orlando RA, Farquhar MG (April 1994). "Functional domains of the receptor-associated protein (RAP)". Proceedings of the National Academy of Sciences of the United States of America. 91 (8): 3161–3165. PMID 7512726.
- Kounnas MZ, Chappell DA, Strickland DK, Argraves WS (July 1993). "Glycoprotein 330, a member of the low density lipoprotein receptor family, binds lipoprotein lipase in vitro". The Journal of Biological Chemistry. 268 (19): 14176–14181. PMID 7686151.
- Kounnas MZ, Loukinova EB, Stefansson S, Harmony JA, Brewer BH, Strickland DK, Argraves WS (June 1995). "Identification of glycoprotein 330 as an endocytic receptor for apolipoprotein J/clusterin". The Journal of Biological Chemistry. 270 (22): 13070–13075. PMID 7768901.
- 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. PMID 7959795.
- Lundgren S, Hjälm G, Hellman P, Ek B, Juhlin C, Rastad J, et al. (June 1994). "A protein involved in calcium sensing of the human parathyroid and placental cytotrophoblast cells belongs to the LDL-receptor protein superfamily". Experimental Cell Research. 212 (2): 344–350. PMID 8187828.
- Moestrup SK, Nielsen S, Andreasen P, Jørgensen KE, Nykjaer A, Røigaard H, et al. (August 1993). "Epithelial glycoprotein-330 mediates endocytosis of plasminogen activator-plasminogen activator inhibitor type-1 complexes". The Journal of Biological Chemistry. 268 (22): 16564–16570. PMID 8344937.
- Hjälm G, Murray E, Crumley G, Harazim W, Lundgren S, Onyango I, et al. (July 1996). "Cloning and sequencing of human gp330, a Ca(2+)-binding receptor with potential intracellular signaling properties". European Journal of Biochemistry. 239 (1): 132–137. PMID 8706697.
- Willnow TE, Hilpert J, Armstrong SA, Rohlmann A, Hammer RE, Burns DK, Herz J (August 1996). "Defective forebrain development in mice lacking gp330/megalin". Proceedings of the National Academy of Sciences of the United States of America. 93 (16): 8460–8464. PMID 8710893.
- Cui S, Verroust PJ, Moestrup SK, Christensen EI (October 1996). "Megalin/gp330 mediates uptake of albumin in renal proximal tubule". The American Journal of Physiology. 271 (4 Pt 2): F900–F907. PMID 8898021.
- Lundgren S, Carling T, Hjälm G, Juhlin C, Rastad J, Pihlgren U, et al. (March 1997). "Tissue distribution of human gp330/megalin, a putative Ca(2+)-sensing protein". The Journal of Histochemistry and Cytochemistry. 45 (3): 383–392. PMID 9071320.
- Birn H, Verroust PJ, Nexo E, Hager H, Jacobsen C, Christensen EI, Moestrup SK (October 1997). "Characterization of an epithelial approximately 460-kDa protein that facilitates endocytosis of intrinsic factor-vitamin B12 and binds receptor-associated protein". The Journal of Biological Chemistry. 272 (42): 26497–26504. PMID 9334227.