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

Abstract

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.

Authors:
; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
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
OSTI Identifier:
1547934
Alternate Identifier(s):
OSTI ID: 1560099
Grant/Contract Number:  
AC02-06CH11357; HL071818; HL122416; CA221289; PF-14-224-01-DMC; 085P1000817; DK20572
Resource Type:
Published Article
Journal Name:
Journal of Structural Biology: X
Additional Journal Information:
Journal Name: Journal of Structural Biology: X Journal Volume: 1 Journal Issue: C; Journal ID: ISSN 2590-1524
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Pleckstrin homology domain; rho guanine nucleotide exchange factor; phosphatidylinositol 3,4,5-trisphosphate; P-Rex

Citation Formats

Cash, Jennifer N., Sharma, Prateek V., and Tesmer, John J. G. Structural and biochemical characterization of the pleckstrin homology domain of the RhoGEF P-Rex2 and its regulation by PIP3. United States: N. p., 2019. Web. doi:10.1016/j.yjsbx.2018.100001.
Cash, Jennifer N., Sharma, Prateek V., & Tesmer, John J. G. Structural and biochemical characterization of the pleckstrin homology domain of the RhoGEF P-Rex2 and its regulation by PIP3. United States. doi:https://doi.org/10.1016/j.yjsbx.2018.100001
Cash, Jennifer N., Sharma, Prateek V., and Tesmer, John J. G. Tue . "Structural and biochemical characterization of the pleckstrin homology domain of the RhoGEF P-Rex2 and its regulation by PIP3". United States. doi:https://doi.org/10.1016/j.yjsbx.2018.100001.
@article{osti_1547934,
title = {Structural and biochemical characterization of the pleckstrin homology domain of the RhoGEF P-Rex2 and its regulation by PIP3},
author = {Cash, Jennifer N. and Sharma, Prateek V. and Tesmer, John J. G.},
abstractNote = {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.},
doi = {10.1016/j.yjsbx.2018.100001},
journal = {Journal of Structural Biology: X},
number = C,
volume = 1,
place = {United States},
year = {2019},
month = {1}
}

Journal Article:
Free Publicly Available Full Text
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DOI: https://doi.org/10.1016/j.yjsbx.2018.100001

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