Structural Organization and Dynamics of Homodimeric Cytohesin Family Arf GTPase Exchange Factors in Solution and on Membranes
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Authors
Das, SanchaitaMalaby, Andrew W.
Nawrotek, Agata
Zhang, Wenhua
Zeghouf, Mahel
Maslen, Sarah
Skehel, Mark
Chakravarthy, Srinivas
Irving, Thomas C.
Bilsel, Osman
Cherfils, Jacqueline
Lambright, David G.
UMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyProgram in Molecular Medicine
Document Type
Journal ArticlePublication Date
2019-12-03Keywords
DLSEM
GEF
HDX
MS
NS
SAXS
SEC
autoinhibition
structure
Biochemistry
Biophysics
Molecular Biology
Nucleic Acids, Nucleotides, and Nucleosides
Structural Biology
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Show full item recordAbstract
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.Source
Structure. 2019 Dec 3;27(12):1782-1797.e7. doi: 10.1016/j.str.2019.09.007. Epub 2019 Oct 7. Link to article on publisher's site
DOI
10.1016/j.str.2019.09.007Permanent Link to this Item
http://hdl.handle.net/20.500.14038/41324PubMed ID
31601460Related Resources
Rights
Copyright 2019 MRC Laboratory of Molecular Biology. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Distribution License
http://creativecommons.org/licenses/by/4.0/ae974a485f413a2113503eed53cd6c53
10.1016/j.str.2019.09.007
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Except where otherwise noted, this item's license is described as Copyright 2019 MRC Laboratory of Molecular Biology. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).