期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 22, 页码 E4360-E4369出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1614066114
关键词
EHD2; caveolae; membrane-reshaping protein; membrane-bound protein structure; infrared reflection-absorption spectroscopy
资金
- Swedish Research Council
- Swedish Foundation for Strategic Research
- Kempe Foundations
- Molecular Infection Medicine Sweden
- European Union [FP7-PEOPLE-2013-IEF 624864]
- Deutsche Forschungsgemeinschaft [FOR1145]
The EH-domain-containing protein 2 (EHD2) is a dynamin-related ATPase that confines caveolae to the cell surface by restricting the scission and subsequent endocytosis of these membrane pits. For this, EHD2 is thought to first bind to the membrane, then to oligomerize, and finally to detach, in a stringently regulated mechanistic cycle. It is still unclear how ATP is used in this process and whether membrane binding is coupled to conformational changes in the protein. Here, we show that the regulatory N-terminal residues and the EH domain keep the EHD2 dimer in an autoinhibited conformation in solution. By significantly advancing the use of infrared reflection-absorption spectroscopy, we demonstrate that EHD2 adopts an open conformation by tilting the helical domains upon membrane binding. We show that ATP binding enables partial insertion of EHD2 into the membrane, where G-domain-mediated oligomerization occurs. ATP hydrolysis is related to detachment of EHD2 from the membrane. Finally, we demonstrate that the regulation of EHD2 oligomerization in a membrane-bound state is crucial to restrict caveolae dynamics in cells.
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