The crystal structure of the RhoA-AKAP-Lbc DH-PH domain complex

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Item Type:	Article
Title:	The crystal structure of the RhoA-AKAP-Lbc DH-PH domain complex
Creators Name:	Abdul Azeez, K.R. and Knapp, S. and Fernandes, J.M.P. and Klussmann, E. and Elkins, J.M.
Abstract:	The RhoGEF domain of AKAP-Lbc (AKAP13) catalyses nucleotide exchange on RhoA and is involved in development of cardiac hypertrophy. The RhoGEF activity of AKAP-Lbc has also been implicated in cancer. We have determined the X-ray crystal structure of the complex between RhoA:GDP and the AKAP-Lbc RhoGEF (DH-PH) domain to 2.1 {Angstrom} resolution. The structure reveals important differences compared to related RhoGEF proteins such as Leukemia-associated RhoGEF. Nucleotide exchange assays comparing the activity of the DH-PH domain to the DH domain alone showed no role for the PH domain in nucleotide exchange, which is explained by the RhoA:AKAP-Lbc structure. Comparison to a structure of the isolated AKAP-Lbc DH domain revealed a change in conformation of the N-terminal 'GEF switch' region upon binding to RhoA. Isothermal titration calorimetry showed that AKAP-Lbc has only micromolar affinity for RhoA which combined with the presence of potential binding pockets for small molecules on AKAP-Lbc raises the possibility of targeting AKAP-Lbc with guanine nucleotide exchange factor inhibitors.
Keywords:	AKAP13, AKAP-Lbc, GTPase, RhoGEF
Source:	Biochemical Journal
ISSN:	0264-6021
Publisher:	Portland Press
Volume:	464
Number:	2
Page Range:	231-239
Date:	1 December 2014
Additional Information:	Copyright © 2014 The Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (CC-BY) (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.
Official Publication:	https://doi.org/10.1042/BJ20140606
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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