UMMS Affiliation

Program in Molecular Medicine; Department of Biochemistry and Molecular Pharmacology

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Document Type



Biochemistry | Biophysics | Molecular Biology | Nucleic Acids, Nucleotides, and Nucleosides | Structural Biology


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.


DLS, EM, GEF, HDX, MS, NS, SAXS, SEC, autoinhibition, structure

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Copyright 2019 MRC Laboratory of Molecular Biology. Published by Elsevier Ltd. This is an open access article under the CC BY license (

DOI of Published Version



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

Journal/Book/Conference Title

Structure (London, England : 1993)

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Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.