Question

What do LDL receptor (LDLR) cytoplasmic domain mutations that cause familial hypercholesterolemia reveal about the receptor-mediated endocytosis (RME) pathway? Based on your knowledge of the entire endocytic process of LDL, are there other proteins in the pathway that if mutated might cause hypercholesterolemia? Explain how and why a mutation in a different protein in the pathway could cause disease. For a person who is homozygous for the NPXY mutation in their LDLR, can you think of a way to fix this individuals uptake of cholesterol?

Answer 1

Mutation in cytosolic domain of LDL receptor reveal that clathrin coated pit formation is a crucial step in receptor mediated endocytosis. The mutant receptor can bind to LDL but is unable to internalize it via clathrin coated pits. This mutant receptor -LDL is found all over the cell surface rather than concentrated in clathrin coated pits. It cannot bind to clathrin molecules. Various Mutant forms of LDL receptors have been extensively studied in fibroblast cell. It was found that four residues - Tyr-X-X- in cytosolic domain of LDL receptor are important for internalization. This sequence bind to 2 subunit of adaptor protein complex . This adaptor protein complex also binds to clathrin. Clathrin forms basket like structure which causes distortion of membrane leading to formation of invaginated pits.Therefore adaptor protein complex acts as link between LDL receptor and clathrin and this association helps in the formation of clathrin coated pits. Mutation in cytosolic domain of LDL receptor prevents the formation of clathrin coated pits. Mutation of tryosine to cysteine can manifest as disease.

Mutations in the adaptor protein can also lead to hypercholerterolemia as it would again prevent the formation clathrin coated pits and prevent internalization of LDL via its receptor. Autosomal recessive hypercholestrolemia is observed in case of adaptor protein mutations.

Statins are used to block cholestrol synthesis. A blockage in cholesterol biosynthesis mainly affects hepatocytes and will reduce the pool of cholestrol required for bile acid synthesis. This will upregulate LDL receptor expression and uptake LDL from blood thereby lowering its level in blood.

Ezetimibe blocks cholesterol uptake by intestine. This will again reduce cholestrol levels in liver leading to increase LDL receptor synthesis.