Publication Date:
2014-07-26
Description:
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 beta2 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4333214/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4333214/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kelly, Bernard T -- Graham, Stephen C -- Liska, Nicole -- Dannhauser, Philip N -- Honing, Stefan -- Ungewickell, Ernst J -- Owen, David J -- 079895/Wellcome Trust/United Kingdom -- 090909/Wellcome Trust/United Kingdom -- 090909/Z/09/Z/Wellcome Trust/United Kingdom -- 098406/Wellcome Trust/United Kingdom -- 098406/Z/12/Z/Wellcome Trust/United Kingdom -- 100140/Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2014 Jul 25;345(6195):459-63. doi: 10.1126/science.1254836.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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. ; Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK. ; Cambridge Institute for Medical Research (CIMR), Department of Clinical Biochemistry, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK. ; Department of Cell Biology, Center of Anatomy, Hannover Medical School, Carl-Neuberg Strasse 1, D-30625 Hannover, Germany. ; Institute of Biochemistry I and Center for Molecular Medicine Cologne, University of Cologne, Joseph-Stelzmann-Strasse 52, 50931 Cologne, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25061211" target="_blank"〉PubMed〈/a〉
Keywords:
Adaptor Protein Complex 2/*chemistry
;
Adaptor Protein Complex beta Subunits/*chemistry
;
Cell Membrane/*chemistry
;
Clathrin/*chemistry
;
Endocytosis
;
Humans
;
Phosphatidylinositol 4,5-Diphosphate/chemistry
;
*Polymerization
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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