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Science. 2014 Jul 25;345(6195):459-63. doi: 10.1126/science.1254836.

Clathrin adaptors. AP2 controls clathrin polymerization with a membrane-activated switch.

Author information

1
Cambridge Institute for Medical Research (CIMR), Department of Clinical Biochemistry, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK. btk1000@cam.ac.uk djo30@cam.ac.uk.
2
Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.
3
Cambridge Institute for Medical Research (CIMR), Department of Clinical Biochemistry, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK.
4
Department of Cell Biology, Center of Anatomy, Hannover Medical School, Carl-Neuberg Strasse 1, D-30625 Hannover, Germany.
5
Institute of Biochemistry I and Center for Molecular Medicine Cologne, University of Cologne, Joseph-Stelzmann-Strasse 52, 50931 Cologne, Germany.

Abstract

Clathrin-mediated endocytosis (CME) is vital for the internalization of most cell-surface proteins. In CME, plasma membrane-binding clathrin adaptors recruit and polymerize clathrin to form clathrin-coated pits into which cargo is sorted. Assembly polypeptide 2 (AP2) is the most abundant adaptor and is pivotal to CME. Here, we determined a structure of AP2 that includes the clathrin-binding β2 hinge and developed an AP2-dependent budding assay. Our findings suggest that an autoinhibitory mechanism prevents clathrin recruitment by cytosolic AP2. A large-scale conformational change driven by the plasma membrane phosphoinositide phosphatidylinositol 4,5-bisphosphate and cargo relieves this autoinhibition, triggering clathrin recruitment and hence clathrin-coated bud formation. This molecular switching mechanism can couple AP2's membrane recruitment to its key functions of cargo and clathrin binding.

Comment in

PMID:
25061211
PMCID:
PMC4333214
DOI:
10.1126/science.1254836
[Indexed for MEDLINE]
Free PMC Article

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