Structural and biochemical characterization of the pleckstrin homology domain of the RhoGEF P-Rex2 and its regulation by PIP3

Cash, Jennifer N.; Sharma, Prateek V.; Tesmer, John J. G.

doi:10.1016/j.yjsbx.2018.100001

Title: Structural and biochemical characterization of the pleckstrin homology domain of the RhoGEF P-Rex2 and its regulation by PIP3

Journal Article · Tue Jan 01 00:00:00 EST 2019 · Journal of Structural Biology: X

DOI:https://doi.org/10.1016/j.yjsbx.2018.100001· OSTI ID:1547934

Cash, Jennifer N.; Sharma, Prateek V.; Tesmer, John J. G.

P-Rex family Rho guanine-nucleotide exchange factors are important regulators of cell motility through their activation of a subset of small GTPases. Both P-Rex1 and P-Rex2 have also been implicated in the progression of certain cancers, including breast cancer and melanoma. Although these molecules display a high level of homology, differences exist in tissue distribution, physiological function, and regulation at the molecular level. Here, we sought to compare the P-Rex2 pleckstrin homology (PH) domain structure and ability to interact with PIP₃ with those of P-Rex1. The 1.9 Å crystal structure of the P-Rex2 PH domain reveals conformational differences in the loop regions, yet biochemical studies indicate that the interaction of the P-Rex2 PH domain with PIP₃ is very similar to that of P-Rex1. Binding of the PH domain to PIP₃ is critical for P-Rex2 activity but not membrane localization, as previously demonstrated for P-Rex1. These studies serve as a starting point in the identification of P-Rex structural features that are divergent between isoforms and could be exploited for the design of P-Rex selective compounds.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC); National Institutes of Health (NIH); American Cancer Society; Michigan Cancer Research Fund; Michigan Economic Development Corporation; Michigan Technology Tri-Corridor; Michigan Diabetes Research and Training Center

Grant/Contract Number:: AC02-06CH11357; HL071818; HL122416; CA221289; PF-14-224-01-DMC; 085P1000817; DK20572

OSTI ID:: 1547934

Alternate ID(s):: OSTI ID: 1560099

Journal Information:: Journal of Structural Biology: X, Journal Name: Journal of Structural Biology: X Vol. 1 Journal Issue: C; ISSN 2590-1524

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
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rho guanine nucleotide exchange factor
phosphatidylinositol 3
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