Endosomal low pH breaks up ligand/megalin complex, allowing the recycling of the unoccupied receptor back to the apical surface, while the ligand is either transported via late endosomal compartments to lysosomes for degradation or transcytosis by early endosomes to the basolateral surface. B) Once the ligand interacts with megalin, the ligand/megalin complex internalizes into the cell and moves to the early endosome. The intracellular tail, with two NPKY and one NPKY-like motif, harbors several Src-homology-3 (SH3) and one Src-homology-2 (SH2) recognition sites. A) Megalin contains a large extracellular domain (~4400 amino acids) with four cysteine-rich ligand-binding regions (red dots) separated by clusters of growth factor repeats (green dots) and YWTD spacer regions (curvy line), and an EGF-like repeat (yellow dot) adjacent to the 22 amino acid transmembrane domain (green rectangle). Megalin molecular structure and endocytic cycle. A long list of structurally and functionally diverse compounds can bind to megalin, such as carrier proteins, lipoproteins, hormones and signaling proteins, enzymes and enzyme inhibitors, immune- and stress-related proteins, drugs, and toxins, among others ( Table SM1). Megalin is characterized by a large extracellular domain that is predicted to be responsible for capturing the ligands from the extracellular fluid, and a cytoplasmic domain that may regulate endocytosis and receptor trafficking ( Figure 1). Megalin (~600 kDa), also known as low-density lipoprotein receptor-related protein 2 (LRP2), is a transmembrane glycoprotein thought to play a relevant role as scavenger receptor in specialized absorptive epithelia in the brain, the eye, the lung, the kidney, and the reproductive tissues, by mediating the non-specific uptake from extracellular fluids such as cerebrospinal fluid, vitreous humor, alveolar fluid, primary urine, or endometrial fluid. The deficiency of megalin, a transmembrane glycoprotein thought to play a relevant role as scavenger receptor in specialized absorptive epithelia, is responsible for the Donnai-Barrow syndrome in humans, as well as for the distinctive eyeball enlargement of certain goldfish strains.
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