Objective "Hypercholesterolemia, high levels of plasma LDL-cholesterol, is a major risk factor for atherosclerosis and premature coronary heart disease (CHD), a leading cause of death in worldwide. The clearance of LDL from the circulation occurs via endocytosis with the LDL-receptor (LDLR) mainly by liver cells. This hepatic recruitment of the LDL-LDLR complex to the clathrin-coated pits is dependent on the endocytic adaptor protein, autosomal recessive hypercholesterolemia (ARH), which recognizes the NPxY internalization signal on the LDLR cytoplasmic tail. Consequently, naturally occurring mutations in either LDLR or in ARH lead to sever hypercholesterolemia and premature onset of CHD. Therefore, studying the molecular interactions ARH forms at the cell surface to facilitate endocytosis of the LDLR is central to our understanding of cholesterol homeostasis.I recently solved a novel crystal structure of the LDLR-ARH interface at atomic resolution. Surprisingly, the structure reveals that the phosphotyrosine-binding (PTB) domain of ARH recognizes a longer portion of the LDLR tail than previously believed, and that ARH has discrete structural determinants for somewhat promiscuous binding of NPxY containing signals of various flanking specificities.To gain a detailed mechanistic understanding for the unique endoctytic function of ARH, this proposal will investigate (1) The molecular basis for receptor recognition by solving crystal structures of ARH with all the receptor tails it is known to bind; (2) The interaction of ARH with phosphoinositides and with cell membrane via tools from cell biology and biochemistry; (3) The interaction of ARH with clathrin and its major endocytic adaptor AP-2 structurally and biochemically.This multidisciplinary approach will significantly extend the molecular knowledge on sorting of LDLR to clathrin-coated pits which is highly significant for cellular physiology and for homeostasis of plasma cholesterol and cardiovascular health." Fields of science engineering and technologymaterials engineeringcrystalsnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesbiological sciencescell biologynatural sciencesbiological sciencesgeneticsmutationmedical and health sciencesbasic medicinephysiologyhomeostasis Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) FP7-PEOPLE-2012-IIF - Marie Curie Action: "International Incoming Fellowships" Call for proposal FP7-PEOPLE-2012-IIF See other projects for this call Funding Scheme MC-IIF - International Incoming Fellowships (IIF) Coordinator TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY EU contribution € 227 231,20 Address SENATE BUILDING TECHNION CITY 32000 Haifa Israel See on map Activity type Higher or Secondary Education Establishments Administrative Contact Mark Davison (Mr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data
