IQGAP Proteins Reveal an Atypical Phosphoinositide (aPI) Binding Domain with a Pseudo C2 Domain Fold

Miles J. Dixon, Alexander Gray, Martijn Schenning, Mark Agacan, Wolfram Tempel, Yufeng Tong, Lyudmila Nedyalkova, Hee-Won Park, Nicholas R. Leslie, Daan M. F. van Aalten, C. Peter Downes, Ian H. Batty

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    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 (PtdInsP3). The binding affinity for PtdInsP3, 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 PtdInsP3 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.

    Original languageEnglish
    Pages (from-to)22483-22496
    Number of pages14
    JournalJournal of Biological Chemistry
    Issue number27
    Publication statusPublished - 29 Jun 2012

    Cite this

    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. F., Downes, C. P., & Batty, I. H. (2012). IQGAP Proteins Reveal an Atypical Phosphoinositide (aPI) Binding Domain with a Pseudo C2 Domain Fold. Journal of Biological Chemistry, 287(27), 22483-22496.