Determinants of G alpha 12 specific interaction in the RhoGEF AKAP-Lbc

Autumn Towne


AKAP-Lbc is a Rho-specific guanine nucleotide exchange factor (RhoGEF) that is stimulated by trimeric G protein alpha subunits of the G12/13 subfamily. Despite lacking a RGS-homology domain that is well characterized as allowing several other RhoGEFs to interact with G12/13 alpha subunits, AKAP-Lbc has been reported as a specific binding partner of G alpha 12. This protein interaction appears to play a role in cardiac hypertrophy as well as heart development. In cardiac hypertrophy, damage to the cardiomyocytes initiates a signaling cascade that results in these cells becoming more fibroblast-like and secreting extracellular matrix proteins, leading to the stiffening of heart tissue. We have identified a G alpha 12 binding region within AKAP-Lbc that shares homology with p114RhoGEF, a protein that also lacks a RGS-homology domain. Based on our initial findings that p114RhoGEF also binds G alpha 12, we aligned these proteins to identify amino acids within the G alpha 12 binding region of AKAP-Lbc that are shared with p114RhoGEF and engineered charge-substitution mutants at these positions. Our examination of these mutants in protein binding assays has revealed several amino acids in AKAP-Lbc that are important in G alpha 12 interaction. Our goal is to use this information to better characterize the structural features of the interaction between G alpha 12 and RhoGEFs which lack RGS-homology domains and ultimately to manipulate this protein interaction to decipher its role in cellular signal transduction.

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