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]
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]
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 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]
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 Donnai-Barrow syndrome. [16]
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]
LRP2 has been shown to associate with the following proteins in the plasma membrane/cytosol of cells:
LRP2 has been shown to bind to the following ligands:
Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a vesicle containing the ingested material. Endocytosis includes pinocytosis and phagocytosis. It is a form of active transport.
Clathrin is a protein that plays a major role in the formation of coated vesicles. Clathrin was first isolated by Barbara Pearse in 1976. It forms a triskelion shape composed of three clathrin heavy chains and three light chains. When the triskelia interact they form a polyhedral lattice that surrounds the vesicle. The protein's name refers to this lattice structure, deriving from Latin clathri meaning lattice. Barbara Pearse named the protein clathrin at the suggestion of Graeme Mitchison, selecting it from three possible options. Coat-proteins, like clathrin, are used to build small vesicles in order to transport molecules within cells. The endocytosis and exocytosis of vesicles allows cells to communicate, to transfer nutrients, to import signaling receptors, to mediate an immune response after sampling the extracellular world, and to clean up the cell debris left by tissue inflammation. The endocytic pathway can be hijacked by viruses and other pathogens in order to gain entry to the cell during infection.
Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membrane can follow this pathway all the way to lysosomes for degradation or can be recycled back to the cell membrane in the endocytic cycle. Molecules are also transported to endosomes from the trans Golgi network and either continue to lysosomes or recycle back to the Golgi apparatus.
The proximal tubule is the segment of the nephron in kidneys which begins from the renal pole of the Bowman's capsule to the beginning of loop of Henle. At this location, the glomerular parietal epithelial cells (PECs) lining bowman’s capsule abruptly transition to proximal tubule epithelial cells (PTECs). The proximal tubule can be further classified into the proximal convoluted tubule (PCT) and the proximal straight tubule (PST).
Receptor-mediated endocytosis (RME), also called clathrin-mediated endocytosis, is a process by which cells absorb metabolites, hormones, proteins – and in some cases viruses – by the inward budding of the plasma membrane (invagination). This process forms vesicles containing the absorbed substances and is strictly mediated by receptors on the surface of the cell. Only the receptor-specific substances can enter the cell through this process.
Michael Stuart Brown ForMemRS NAS AAA&S APS is an American geneticist and Nobel laureate. He was awarded the Nobel Prize in Physiology or Medicine with Joseph L. Goldstein in 1985 for describing the regulation of cholesterol metabolism.
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.
Retromer is a complex of proteins that has been shown to be important in recycling transmembrane receptors from endosomes to the trans-Golgi network (TGN) and directly back to the plasma membrane. Mutations in retromer and its associated proteins have been linked to Alzheimer's and Parkinson's diseases.
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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.
AP-2 complex subunit mu is a protein that in humans is encoded by the AP2M1 gene.
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.
Disabled homolog 2 is a protein that in humans is encoded by the DAB2 gene.
The CLCN5 gene encodes the chloride channel Cl-/H+ exchanger ClC-5. ClC-5 is mainly expressed in the kidney, in particular in proximal tubules where it participates to the uptake of albumin and low-molecular-weight proteins, which is one of the principal physiological role of proximal tubular cells. Mutations in the CLCN5 gene cause an X-linked recessive nephropathy named Dent disease characterized by excessive urinary loss of low-molecular-weight proteins and of calcium (hypercalciuria), nephrocalcinosis and nephrolithiasis.
Sodium–hydrogen antiporter 3 also known as sodium–hydrogen exchanger 3 (NHE3) or solute carrier family 9 member 3 (SLC9A3) is a protein that in humans is encoded by the SLC9A3 gene.
GIPC PDZ domain containing family, member 1 (GIPC1) is a protein that in humans is encoded by the GIPC1 gene. GIPC was originally identified as it binds specifically to the C terminus of RGS-GAIP, a protein involved in the regulation of G protein signaling. GIPC is an acronym for "GAIP Interacting Protein C-terminus". RGS proteins are "Regulators of G protein Signaling" and RGS-GAIP is a "GTPase Activator protein for Gαi/Gαq", which are two major subtypes of Gα proteins. The human GIPC1 molecule is 333 amino acids or about 36 kDa in molecular size and consists of a central PDZ domain, a compact protein module which mediates specific protein-protein interactions. The RGS-GAIP protein interacts with this domain and many other proteins interact here or at other parts of the GIPC1 molecule. As a result, GIPC1 was independently discovered by several other groups and has a variety of alternate names, including synectin, C19orf3, RGS19IP1 and others. The GIPC1 gene family in mammals consisting of three members, so the first discovered, originally named GIPC, is now generally called GIPC1, with the other two being named GIPC2 and GIPC3. The three human proteins are about 60% identical in protein sequence. GIPC1 has been shown to interact with a variety of other receptor and cytoskeletal proteins including the GLUT1 receptor, ACTN1, KIF1B, MYO6, PLEKHG5, SDC4/syndecan-4, SEMA4C/semaphorin-4 and HTLV-I Tax. The general function of GIPC family proteins therefore appears to be mediating specific interactions between proteins involved in G protein signaling and membrane translocation.
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Lipids: lipoprotein particle metabolism | ||
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| Lipoprotein particle classes and subclasses |
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| Apolipoproteins | ||
| Extracellular enzymes | ||
| Lipid transfer proteins | ||
| Cell surface receptors | ||
| ATP-binding cassette transporter | ||