Structural and Biochemical Characterization of the Catalytic Core of the Metastatic Factor P-Rex1 and Its Regulation by PtdIns(3,4,5)P3

Cash, Jennifer N.; Davis, Ellen M.; Tesmer, John J. G.

doi:10.1016/j.str.2016.02.022

Title: Structural and Biochemical Characterization of the Catalytic Core of the Metastatic Factor P-Rex1 and Its Regulation by PtdIns(3,4,5)P3

Journal Article · Sun May 01 00:00:00 EDT 2016 · Structure

DOI:https://doi.org/10.1016/j.str.2016.02.022· OSTI ID:1355064

Cash, Jennifer N.; Davis, Ellen M.; Tesmer, John J. G.

Phosphatidylinositol 3,4,5-trisphosphate (PIP3)-dependent Rac exchanger 1 (P-Rex1) is a Rho guanine nucleotide exchange factor synergistically activated by PIP₃ and Gβγ that plays an important role in the metastasis of breast, prostate, and skin cancer, making it an attractive therapeutic target. However, the molecular mechanisms behind P-Rex1 regulation are poorly understood. We determined structures of the P-Rex1 pleckstrin homology (PH) domain bound to the headgroup of PIP₃ and resolved that PIP₃ binding to the PH domain is required for P-Rex1 activity in cells but not for membrane localization, which points to an allosteric activation mechanism by PIP₃. We also determined structures of the P-Rex1 tandem Dbl homology/PH domains in complexes with two of its substrate GTPases, Rac1 and Cdc42. Collectively, this study provides important molecular insights into P-Rex1 regulation and tools for targeting the PIP₃-binding pocket of P-Rex1 with a new generation of cancer chemotherapeutic agents.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC); National Institutes of Health (NIH); Michigan Economic Development Corp.; Michigan Technology Tri-Corridor

Grant/Contract Number:: AC02-06CH11357; HL086865; HL122416; 085P1000817; DK20572

OSTI ID:: 1355064

Alternate ID(s):: OSTI ID: 1255291

Journal Information:: Structure, Journal Name: Structure Vol. 24 Journal Issue: 5; ISSN 0969-2126

Publisher:: ElsevierCopyright Statement

Country of Publication:: United Kingdom

Language:: English

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Cited by: 24 works

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Title: Structural and Biochemical Characterization of the Catalytic Core of the Metastatic Factor P-Rex1 and Its Regulation by PtdIns(3,4,5)P3

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