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

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 ?2 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.

SUBMITTER: Kelly BT

PROVIDER: S-EPMC4333214 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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

Kelly Bernard T BT Graham Stephen C SC Liska Nicole N Dannhauser Philip N PN Höning Stefan S Ungewickell Ernst J EJ Owen David J DJ

Science (New York, N.Y.) 20140701 6195

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 mechani ...[more]

PMID: 25061211

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