Low density lipoprotein receptor-related protein 2 also known as LRP-2 or megalin is a protein which in humans is encoded by the LRP2gene.[5][6][7]
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 epithelialcells. LRP2 is an approximately 600kDa (4665 amino acids) transmembrane glycoprotein with structural similarities to the low density lipoprotein receptor (LDLR).[9] LRP2 has a NPXY motif that is the binding site for Dab2 to initiate clathrin-mediated endocytosis.[10] LRP2 forms a homodimer that changes conformation in response to pH.[11] At pH 7.5 (extracellular pH), LRP2 is considered active, with the leucine loops in an open conformation to allow ligands to bind.[11] At acidic endosomal pHs, the leucine loops collapse to prevent ligands binding.[11]
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]
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:
^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. PMID7959795.
^Gallagher H, Oleinikov AV, Fenske C, Newman DJ (March 2004). "The adaptor disabled-2 binds to the third psi xNPxY sequence on the cytoplasmic tail of megalin". Biochimie. 86 (3): 179–182. doi:10.1016/j.biochi.2004.03.001. PMID15134832.
Christensen EI, Birn H (April 2002). "Megalin and cubilin: multifunctional endocytic receptors". Nature Reviews. Molecular Cell Biology. 3 (4): 256–266. doi:10.1038/nrm778. PMID11994745. S2CID21893726.
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. doi:10.1111/j.1440-1797.2005.00453.x. PMID16174284. S2CID42737684.
Fisher CE, Howie SE (August 2006). "The role of megalin (LRP-2/Gp330) during development". Developmental Biology. 296 (2): 279–297. doi:10.1016/j.ydbio.2006.06.007. PMID16828734.
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. doi:10.1177/40.10.1382088. PMID1382088. S2CID24323611.
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. Bibcode:1989Sci...244.1163R. doi:10.1126/science.2786251. PMID2786251.
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. PMID7959795.
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. doi:10.1006/excr.1994.1153. PMID8187828.
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. doi:10.1152/ajprenal.1996.271.4.F900. PMID8898021.
