4EZA

Crystal structure of the atypical phosphoinositide (aPI) binding domain of IQGAP2

Summary for 4EZA

• Entry DOI: 10.2210/pdb4eza/pdb
• Descriptor: Ras GTPase-activating-like protein IQGAP2 (2 entities in total)
• Functional Keywords: gap, structural genomics consortium, sgc, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 26464.69

Authors

Van Aalten, D.M.F.,Dixon, M.J.,Gray, A.,Schenning, M.,Agacan, M.,Leslie, N.R.,Downes, C.P.,Batty, I.H.,Nedyalkova, L.,Tempel, W.,Tong, Y.,Zhong, N.,Crombet, L.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Weigelt, J.,Bochkarev, A.,Park, H.,Structural Genomics Consortium (SGC) (deposition date: 2012-05-02, release date: 2012-05-16, Last modification date: 2024-02-28)

Primary citation

Dixon, M.J.,Gray, A.,Schenning, M.,Agacan, M.,Tempel, W.,Tong, Y.,Nedyalkova, L.,Park, H.W.,Leslie, N.R.,van Aalten, D.M.,Downes, C.P.,Batty, I.H.
IQGAP Proteins Reveal an Atypical Phosphoinositide (aPI) Binding Domain with a Pseudo C2 Domain Fold.
J.Biol.Chem., 287:22483-22496, 2012

PubMed Abstract: Class I phosphoinositide (PI) 3-kinases act through effector proteins whose 3-PI selectivity is mediated by a limited repertoire of structurally defined, lipid recognition domains. We describe here the lipid preferences and crystal structure of a new class of PI binding modules exemplified by select IQGAPs (IQ motif containing GTPase-activating proteins) known to coordinate cellular signaling events and cytoskeletal dynamics. This module is defined by a C-terminal 105-107 amino acid region of which IQGAP1 and -2, but not IQGAP3, binds preferentially to phosphatidylinositol 3,4,5-trisphosphate (PtdInsP(3)). The binding affinity for PtdInsP(3), together with other, secondary target-recognition characteristics, are comparable with those of the pleckstrin homology domain of cytohesin-3 (general receptor for phosphoinositides 1), an established PtdInsP(3) effector protein. Importantly, the IQGAP1 C-terminal domain and the cytohesin-3 pleckstrin homology domain, each tagged with enhanced green fluorescent protein, were both re-localized from the cytosol to the cell periphery following the activation of PI 3-kinase in Swiss 3T3 fibroblasts, consistent with their common, selective recognition of endogenous 3-PI(s). The crystal structure of the C-terminal IQGAP2 PI binding module reveals unexpected topological similarity to an integral fold of C2 domains, including a putative basic binding pocket. We propose that this module integrates select IQGAP proteins with PI 3-kinase signaling and constitutes a novel, atypical phosphoinositide binding domain that may represent the first of a larger group, each perhaps structurally unique but collectively dissimilar from the known PI recognition modules.

PubMed: 22493426
DOI: 10.1074/jbc.M112.352773

Experimental method

X-RAY DIFFRACTION (1.5 Å)