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

Informations projet

ARH-ENDO

N° de convention de subvention: 321877

Projet clôturé

Date de début

Date de fin

Financé au titre de

• Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)

Coût total € 100 000,00

Contribution de l’UE € 100 000,00

Coordonné par

TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY
Israel

Objectif

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.

Champ scientifique

Not validated

• engineering and technology › materials engineering › crystals
• medical and health sciences › clinical medicine › cardiology › cardiovascular diseases › arteriosclerosis
• natural sciences › biological sciences › biochemistry › biomolecules › proteins
• natural sciences › biological sciences › cell biology
• medical and health sciences › basic medicine › physiology › homeostasis

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)

Thème(s)

• FP7-PEOPLE-2012-CIG - Marie-Curie Action: "Career Integration Grants"

Appel à propositions

FP7-PEOPLE-2012-CIG
Voir d’autres projets de cet appel

Régime de financement

MC-CIG - Support for training and career development of researcher (CIG)

Coordinateur

TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY

• Contribution de l’UE: € 100 000,00
• Adresse: SENATE BUILDING TECHNION CITY ; 32000 Haifa ; Israël
• Type d’activité: Higher or Secondary Education Establishments
• Contact administratif: Mark Davison (Mr.)
• Coût total: Aucune donnée