NDLI: Activation of Leukemia-associated RhoGEF by Gα13 with Significant Conformational Rearrangements in the Interface* S⃞

Content Provider	PubMed Central
Author	Suzuki, Nobuchika Tsumoto, Kouhei Hajicek, Nicole Daigo, Kenji Tokita, Reiko Minami, Shiro Kodama, Tatsuhiko Takao, Hamakubo Kozasa, Tohru
Abstract	The transient protein-protein interactions induced by guanine nucleotide-dependent conformational changes of G proteins play central roles in G protein-coupled receptor-mediated signaling systems. Leukemia-associated RhoGEF (LARG), a guanine nucleotide exchange factor for Rho, contains an RGS homology (RH) domain and Dbl homology/pleckstrin homology (DH/PH) domains and acts both as a GTPase-activating protein (GAP) and an effector for Gα13. However, the molecular mechanism of LARG activation upon Gα13 binding is not yet well understood. In this study, we analyzed the Gα13-LARG interaction using cellular and biochemical methods, including a surface plasmon resonance (SPR) analysis. The results obtained using various LARG fragments demonstrated that active Gα13 interacts with LARG through the RH domain, DH/PH domains, and C-terminal region. However, an alanine substitution at the RH domain contact position in Gα13 resulted in a large decrease in affinity. Thermodynamic analysis revealed that binding of Gα13 proceeds with a large negative heat capacity change (ΔCp°), accompanied by a positive entropy change (ΔS°). These results likely indicate that the binding of Gα13 with the RH domain triggers conformational rearrangements between Gα13 and LARG burying an exposed hydrophobic surface to create a large complementary interface, which facilitates complex formation through both GAP and effector interfaces, and activates the RhoGEF. We propose that LARG activation is regulated by an induced-fit mechanism through the GAP interface of Gα13.
Related Links	http://dx.doi.org/10.1074/jbc.m804073200
Ending Page	5009
Page Count	10
Starting Page	5000
File Format	PDF
ISSN	00219258
e-ISSN	1083351X
Journal	The Journal of Biological Chemistry
Issue Number	8
Volume Number	284
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2009-02-20
Access Restriction	Open
Rights Holder	American Society for Biochemistry and Molecular Biology
Subject Keyword	Cell Biology Biochemistry Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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Activation of Leukemia-associated RhoGEF by Gα13 with Significant Conformational Rearrangements in the Interface

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