IQGAP proteins reveal an atypical phosphoinositide (aPI) binding domain with a pseudo C2 domain fold |
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Authors: | Dixon Miles J Gray Alexander Schenning Martijn Agacan Mark Tempel Wolfram Tong Yufeng Nedyalkova Lyudmila Park Hee-Won Leslie Nicholas R van Aalten Daan M F Downes C Peter Batty Ian H |
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Institution: | Division of Cell Signalling and Immunology, College of Life Sciences, University of Dundee, Dow St., Dundee DD1 5EH, Scotland, United Kingdom. |
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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. |
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Keywords: | Cell signaling Crystal Structure PI 3-Kinase (PI3K) Protein Domains Receptors C2 Domain IQGAP PH Domain PtdInsP3 aPI Domain |
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