Question

Discuss all aspects of the LDL-R pathway – the receptor’s structure, interactions with the LDLs, the structure of the LDLs and where made, their endocytosis, recycling of receptors, role of pH – how let go of LDL, and fate of LDL within the cell.

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Answer 1

Answer: Low density lipoprotein (LDL) receptors represents a group of structurally related transmembrane proteins that mediates the endocytosis of cholesterol rich LDL. Low density lipoprotein (lDL) transports cholesterol from liver to peripheral tissues. Its outer ssurface consists of a single layer of phospholipids and cholesterol, in which the apoprotein apo B100 remains embedded. Cholesterol is present in the inside non polar core. LDL receptorss are present on all cells but most abundant in hepatic cells. The LDL receptor is a polypeptide of 839 amino acids. It belongs to the LDLR family and contains several functionally distinct domains which includes three 3 EGF like domains which are three growth factor repeats, 7 LDL-R class A domains which is present at the N-terminal region of the receptor that is responsible for ligand binding and 6 LDL-R class B domains that is responsible for pH dependent conformational shift enabling the bound LDL to be released in the late endosomes. The cytosolic C terminal domains contains 50 amino acids and a signaling sequence crucial for internalization and receptor mediated endocytosis. Any mutation in this amino acid sequence may result in disrupture of the ability of the receptor to be incorporated into clathrin coated pits.

LDL receptors are located in specialized regions called clathrin coated pits of the plasma membrane. It recognizes the apo B100 protein embedded in the outer phospholipid layer of LDL and the apoE protein found in the chylomicron remnants and VLDL. An extracellular domain is responsible for apoB-100/apoE binding, while the intracellular domain is responsible for the clustering of LDL receptors into regions of the plasma membrane called coated pits. When the apoB-100 binds to the apoB-100 receptor, the receptor-lDL complex is internalized by endocytosis and transported as a coated vesicles. It is then encountered by early endosomes, present at the periphery of the cell to become uncoated vesicles where the clathrin is removed at a mildly acidic pH. Then the LDL-bound receptor complex is encountered by late endosomes with a pH of 5 or below and it is this low pH which triggered the dissociation of LDL particles from their receptor. The spherical part of the late endosome with LDL particles thus formed, are transferred to lysosomes where they fuse with it. As a result, the LDL particle, along with apoproteins and cholesterol ester are hydrolyzed by lysosomal hydrolases, working at pH 4.4, forming amino acids are free cholesterol. The free cholesterol is either incorporated into plasma membranes or esterified and stored within the cell. On the other hand, the intact receptors are recycled back to the cell surface, once again to mediate the internalization of LDL molecules via the tubular portion of late endosomes.