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Title: Structural Basis and Mechanism of Autoregulation in 3-Phosphoionsitide-Dependent Grp1 Family Arf GTPase Exchange Factors

Abstract

Arf GTPases regulate membrane trafficking and actin dynamics. Grp1, ARNO, and Cytohesin-1 comprise a family of phosphoinositide-dependent Arf GTPase exchange factors with a Sec7-pleckstrin homology (PH) domain tandem. Here, we report that the exchange activity of the Sec7 domain is potently autoinhibited by conserved elements proximal to the PH domain. The crystal structure of the Grp1 Sec7-PH tandem reveals a pseudosubstrate mechanism of autoinhibition in which the linker region between domains and a C-terminal amphipathic helix physically block the docking sites for the switch regions of Arf GTPases. Mutations within either element result in partial or complete activation. Critical determinants of autoinhibition also contribute to insulin-stimulated plasma membrane recruitment. Autoinhibition can be largely reversed by binding of active Arf6 to Grp1 and by phosphorylation of tandem PKC sites in Cytohesin-1. These observations suggest that Grp1 family GEFs are autoregulated by mechanisms that depend on plasma membrane recruitment for activation.

Authors:
; ; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Lab. (BNL), Upton, NY (United States). National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
959937
Report Number(s):
BNL-82923-2009-JA
TRN: US201016%%1081
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Journal Name:
Molecular Cell
Additional Journal Information:
Journal Volume: 28; Journal Issue: 4
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; ACTIN; CRYSTAL STRUCTURE; MEMBRANES; MUTATIONS; PHOSPHORYLATION; PLASMA; GTP-ASES; national synchrotron light source

Citation Formats

DiNitto, J, Delprato, A, Lee, M, Cronin, T, Huang, S, Guilherme, A, Czech, M, and Lambright, D. Structural Basis and Mechanism of Autoregulation in 3-Phosphoionsitide-Dependent Grp1 Family Arf GTPase Exchange Factors. United States: N. p., 2007. Web. doi:10.1016/j.molcel.2007.09.017.
DiNitto, J, Delprato, A, Lee, M, Cronin, T, Huang, S, Guilherme, A, Czech, M, & Lambright, D. Structural Basis and Mechanism of Autoregulation in 3-Phosphoionsitide-Dependent Grp1 Family Arf GTPase Exchange Factors. United States. https://doi.org/10.1016/j.molcel.2007.09.017
DiNitto, J, Delprato, A, Lee, M, Cronin, T, Huang, S, Guilherme, A, Czech, M, and Lambright, D. 2007. "Structural Basis and Mechanism of Autoregulation in 3-Phosphoionsitide-Dependent Grp1 Family Arf GTPase Exchange Factors". United States. https://doi.org/10.1016/j.molcel.2007.09.017.
@article{osti_959937,
title = {Structural Basis and Mechanism of Autoregulation in 3-Phosphoionsitide-Dependent Grp1 Family Arf GTPase Exchange Factors},
author = {DiNitto, J and Delprato, A and Lee, M and Cronin, T and Huang, S and Guilherme, A and Czech, M and Lambright, D},
abstractNote = {Arf GTPases regulate membrane trafficking and actin dynamics. Grp1, ARNO, and Cytohesin-1 comprise a family of phosphoinositide-dependent Arf GTPase exchange factors with a Sec7-pleckstrin homology (PH) domain tandem. Here, we report that the exchange activity of the Sec7 domain is potently autoinhibited by conserved elements proximal to the PH domain. The crystal structure of the Grp1 Sec7-PH tandem reveals a pseudosubstrate mechanism of autoinhibition in which the linker region between domains and a C-terminal amphipathic helix physically block the docking sites for the switch regions of Arf GTPases. Mutations within either element result in partial or complete activation. Critical determinants of autoinhibition also contribute to insulin-stimulated plasma membrane recruitment. Autoinhibition can be largely reversed by binding of active Arf6 to Grp1 and by phosphorylation of tandem PKC sites in Cytohesin-1. These observations suggest that Grp1 family GEFs are autoregulated by mechanisms that depend on plasma membrane recruitment for activation.},
doi = {10.1016/j.molcel.2007.09.017},
url = {https://www.osti.gov/biblio/959937}, journal = {Molecular Cell},
number = 4,
volume = 28,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}