Structural Determinants of Phosphoinositide Recognition by Grp1 Family Pleckstrin Homology Domains: a Dissertation

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Document Type

Doctoral Dissertation


Graduate School of Biomedical Sciences


Membrane Microdomains; Membrane Microdomains; GTPase-Activating Proteins; Inositol Phosphates; Phosphatidylinositol Phosphates; Receptors, Cytoplasmic and Nuclear; Alternative Splicing; Academic Dissertations; Dissertations, UMMS


Pleckstrin homology (PH) domains, which play an essential role in membrane trafficking and signal transduction, recognize phosphoinositides with a diverse range of affinities and specificities. The PH domains of the Grp1 family of Arf GTPase exchange factors recognize a select group of phosphoinositides with dramatic differences in specificity, despite 90% sequence identity. The work described in this thesis has focused on the structural basis for these differences. The structure of the Grp1 PH domain revealed structural determinants for phosphoinositide recognition. Through a wide range of crystallographic and biochemical means, the structural basis that accounts for the differential binding affinities amongst the Grp1 family PH domains has also been determined. Furthermore, examination of the structural details of these PH domains bound to different inositol phosphate groups have aided in understanding the structural mechanisms by which all PH domains recognize phosphoinositides.


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