ARH-ENDO

Mechanism of Endocytosis of the Ldl-Receptor via the Autosomal Recessive Hypercholesterolemia protein

Coordinatore	TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY    more  Organization address address: TECHNION CITY - SENATE BUILDING city: HAIFA postcode: 32000 contact info Titolo: Mr. Nome: Mark Cognome: Davison Email: send email Telefono: +972 4 829 3097 Fax: +972 4 823 2958
Nazionalità Coordinatore	Israel [IL]
Totale costo	100˙000 €
EC contributo	100˙000 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-2012-CIG
Funding Scheme	MC-CIG
Anno di inizio	0
Periodo (anno-mese-giorno)	0000-00-00   -   0000-00-00

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY  Organization address address: TECHNION CITY - SENATE BUILDING city: HAIFA postcode: 32000 contact info Titolo: Mr. Nome: Mark Cognome: Davison Email: send email Telefono: +972 4 829 3097 Fax: +972 4 823 2958	IL (HAIFA)	coordinator	100˙000.00

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 Obiettivo del progetto (Objective)

'Hypercholesterolemia, high levels of plasma LDL-cholesterol, is a major risk factor for atherosclerosis and premature coronary heart disease (CHD), the leading cause of death in developed countries. 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). 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 is central to our understanding of LDL internalization and cholesterol homeostasis. Despite large body of structural data on the ecto-domain of LDLR, the structures of either ARH or the LDLR tail are unknown. To gain a detailed mechanistic understanding for the unique function of ARH, this proposal will investigate (1) The molecular basis for receptor recognition by solving crystal structures of ARH with receptor tails; (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. The multidisciplinary approach proposed here will significantly extends the molecular knowledge on sorting of LDLR to clathrin-coated pits which is highly significant for cellular physiology and for catabolism of plasma cholesterol and cardiovascular health.'