2R09

Crystal Structure of Autoinhibited Form of Grp1 Arf GTPase Exchange Factor

Summary for 2R09

• Entry DOI: 10.2210/pdb2r09/pdb
• Related: 2r0d
• Descriptor: Cytohesin-3, SULFATE ION, INOSITOL-(1,3,4,5)-TETRAKISPHOSPHATE, ... (6 entities in total)
• Functional Keywords: autoinhibition, grp1, pip3, arf, 3-phosphoinositide, pleckstrin homology domain, guanine-nucleotide releasing factor, signaling protein
• Biological source: Mus musculus (house mouse)
• Cellular location: Cell membrane (By similarity): O08967
• Total number of polymer chains: 2
• Total formula weight: 83897.29

Authors

DiNitto, J.P.,Delprato, A.,Gabe Lee, M.T.,Cronin, T.C.,Huang, S.,Guilherme, A.,Czech, M.P.,Lambright, D.G. (deposition date: 2007-08-17, release date: 2007-12-04, Last modification date: 2024-10-30)

Primary citation

DiNitto, J.P.,Delprato, A.,Gabe Lee, M.T.,Cronin, T.C.,Huang, S.,Guilherme, A.,Czech, M.P.,Lambright, D.G.
Structural Basis and Mechanism of Autoregulation in 3-Phosphoinositide-Dependent Grp1 Family Arf GTPase Exchange Factors.
Mol.Cell, 28:569-583, 2007

PubMed 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.

PubMed: 18042453
DOI: 10.1016/j.molcel.2007.09.017

Experimental method

X-RAY DIFFRACTION (1.9 Å)