LDL receptor-mediated endocytic uptake — apoB-100 ligand, LDLR internalization and recycling, PCSK9 degradation control

Low-density lipoprotein (LDL) carries most plasma cholesterol and is cleared mainly by hepatocyte LDL receptors. Each LDL particle contains one apolipoprotein B-100 molecule, whose receptor-binding region is the ligand for the cysteine-rich ligand-binding repeats of the LDL receptor (LDLR) at the cell surface. LDLR-LDL complexes cluster in clathrin-coated pits through the LDLR cytoplasmic NPxY motif (with the adaptor LDLRAP1/ARH in liver) and are internalized by receptor-mediated endocytosis. In the acidic early endosome the receptor releases LDL, which proceeds to lysosomes where cholesteryl esters are hydrolysed and free cholesterol is delivered to the cell; the empty receptor recycles to the plasma membrane for further rounds. Secreted PCSK9 binds the LDLR EGF-A repeat and, after co-internalization, prevents the receptor's acid-induced conformational change so that it is routed to lysosomes and degraded instead of recycling, lowering receptor number and LDL clearance (IDOL/MYLIP provides an intracellular, ubiquitin-dependent degradation route). Loss of LDLR, of the apoB-100 receptor-binding region, or of LDLRAP1, or gain of function of PCSK9, causes familial hypercholesterolaemia; PCSK9 loss of function lowers LDL cholesterol and is the target of PCSK9-inhibitor therapy.