Journal
STRUCTURE
Volume 27, Issue 12, Pages 1782-+Publisher
CELL PRESS
DOI: 10.1016/j.str.2019.09.007
Keywords
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Funding
- NIH [GM056324]
- DOE Office of Science [DE-AC02-06CH11357]
- National Institute of General Medical Sciences of the NIH [9 P41 GM103622]
- Institut National Du Cancer [INCa 2014-160]
- Fondation pour la Recherche Medicale [DEQ20150331694]
- Agence Nationale de la Recherche [14-CE09-0028]
- European Biophysical Societies' Association
- MRC [MC_U105184326] Funding Source: UKRI
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Membrane dynamic processes require Arf GTPase activation by guanine nucleotide exchange factors (GEFs) with a Sec7 domain. Cytohesin family Arf GEFs function in signaling and cell migration through Arf GTPase activation on the plasma membrane and endosomes. In this study, the structural organization of two cytohesins (Grp1 and ARNO) was investigated in solution by size exclusion-small angle X-ray scattering and negative stain-electron microscopy and on membranes by dynamic light scattering, hydrogen-deuterium exchange-mass spectrometry and guanosine diphosphate (GDP)/guanosine triphosphate (GTP) exchange assays. The results suggest that cytohesins form elongated dimers with a central coiled coil and membrane-binding pleckstrin-homology (PH) domains at opposite ends. The dimers display significant conformational heterogeneity, with a preference for compact to intermediate conformations. Phosphoinositide-dependent membrane recruitment is mediated by one PH domain at a time and alters the conformational dynamics to prime allosteric activation by Arf-GTP. A structural model for membrane targeting and allosteric activation of full-length cytohesin dimers is discussed.
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