The molecular mechanism for the genetic disorder familial defective apolipoprotein B100

Familial defective apolipoprotein B100 (FDB) is a genetic disorder in which low density lipoproteins (LDL) bind defectively to the LDL receptor, resul ting in hypercholesterolemia and premature atherosclerosis. FDB is caused b y a mutation (R3500Q) that changes the conformation of apolipoprotein (apo) B100 near the receptor-binding site. Pie previously showed that arginine, not simply a positive charge, at residue 3500 is essential for normal recep tor binding and that the carboxyl terminus of apoB100 is necessary for muta tions affecting arginine 3500 to disrupt LDL receptor binding. Thus, normal receptor binding involves an interaction between arginine 3500 and tryptop han 4369 in the carboxyl tail of apoB100. W4369Y LDL and R3500Q LDL isolate d from transgenic mice had identically defective LDL binding and a higher a ffinity for the monoclonal antibody MB47, which has an epitope flanking res idue 3500. We conclude that arginine 3500 interacts with tryptophan 4369 an d facilitates the conformation of apoB100 required for normal receptor bind ing of LDL. From our findings, we developed a model that explains how the c arboxyl terminus of apoB100 interacts with the backbone of apoB100 that enw raps the LDL particle. Our model also explains how all known ligand-defecti ve mutations in apoB100, including a newly discovered R3480W mutation in ap oB100, cause defective receptor binding.