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Title: Structural Dynamics Control Allosteric Activation of Cytohesin Family Arf GTPase Exchange Factors

Abstract

Membrane dynamic processes including vesicle biogenesis depend on Arf guanosine triphosphatase (GTPase) activation by guanine nucleotide exchange factors (GEFs) containing a catalytic Sec7 domain and a membrane-targeting module such as a pleckstrin homology (PH) domain. The catalytic output of cytohesin family Arf GEFs is controlled by autoinhibitory interactions that impede accessibility of the exchange site in the Sec7 domain. These restraints can be relieved through activator Arf-GTP binding to an allosteric site comprising the PH domain and proximal autoinhibitory elements (Sec7-PH linker and C-terminal helix). Small-angle X-ray scattering and negative-stain electron microscopy were used to investigate the structural organization and conformational dynamics of cytohesin-3 (Grp1) in autoinhibited and active states. The results support a model in which hinge dynamics in the autoinhibited state expose the activator site for Arf-GTP binding, while subsequent C-terminal helix unlatching and repositioning unleash conformational entropy in the Sec7-PH linker to drive exposure of the exchange site.

Authors:
; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1418034
Resource Type:
Journal Article
Resource Relation:
Journal Name: Structure; Journal Volume: 26; Journal Issue: 1
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Malaby, Andrew W., Das, Sanchaita, Chakravarthy, Srinivas, Irving, Thomas C., Bilsel, Osman, and Lambright, David G. Structural Dynamics Control Allosteric Activation of Cytohesin Family Arf GTPase Exchange Factors. United States: N. p., 2018. Web. doi:10.1016/j.str.2017.11.019.
Malaby, Andrew W., Das, Sanchaita, Chakravarthy, Srinivas, Irving, Thomas C., Bilsel, Osman, & Lambright, David G. Structural Dynamics Control Allosteric Activation of Cytohesin Family Arf GTPase Exchange Factors. United States. doi:10.1016/j.str.2017.11.019.
Malaby, Andrew W., Das, Sanchaita, Chakravarthy, Srinivas, Irving, Thomas C., Bilsel, Osman, and Lambright, David G. Mon . "Structural Dynamics Control Allosteric Activation of Cytohesin Family Arf GTPase Exchange Factors". United States. doi:10.1016/j.str.2017.11.019.
@article{osti_1418034,
title = {Structural Dynamics Control Allosteric Activation of Cytohesin Family Arf GTPase Exchange Factors},
author = {Malaby, Andrew W. and Das, Sanchaita and Chakravarthy, Srinivas and Irving, Thomas C. and Bilsel, Osman and Lambright, David G.},
abstractNote = {Membrane dynamic processes including vesicle biogenesis depend on Arf guanosine triphosphatase (GTPase) activation by guanine nucleotide exchange factors (GEFs) containing a catalytic Sec7 domain and a membrane-targeting module such as a pleckstrin homology (PH) domain. The catalytic output of cytohesin family Arf GEFs is controlled by autoinhibitory interactions that impede accessibility of the exchange site in the Sec7 domain. These restraints can be relieved through activator Arf-GTP binding to an allosteric site comprising the PH domain and proximal autoinhibitory elements (Sec7-PH linker and C-terminal helix). Small-angle X-ray scattering and negative-stain electron microscopy were used to investigate the structural organization and conformational dynamics of cytohesin-3 (Grp1) in autoinhibited and active states. The results support a model in which hinge dynamics in the autoinhibited state expose the activator site for Arf-GTP binding, while subsequent C-terminal helix unlatching and repositioning unleash conformational entropy in the Sec7-PH linker to drive exposure of the exchange site.},
doi = {10.1016/j.str.2017.11.019},
journal = {Structure},
number = 1,
volume = 26,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2018},
month = {Mon Jan 01 00:00:00 EST 2018}
}