MECHANISM OF GALPHA-13 REGULATED RHOGEF ACTIVITY OF P115RHOGEF

$6,487P41FY2009RRNIH

Illinois Institute Of Technology, Chicago IL

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. p115RhoGEF (p115) represents a direct link between the G12 class heterotrimeric G proteins and the small GTPase Rho. p115 (102 kDa) is both a negative regulator and a downstream effector for Galpha-13 (Ga13, 42 kDa). At its N-terminus, p115 possesses a RhoGEF-RGS (rgRGS) domain that functions as a GTPase activating protein (GAP) towards Ga13. Binding to Ga13 also stimulates its Guanine Nucleotide Exchange (GEF) activity towards RhoA. The GEF activity of p115 is carried out by the tandem DH and PH domains, which are separated from the N-terminal rgRGS domain by a 150 residue linker region. Crystal structures of the complex of the rgRGS domain with Ga13 and the DH-PH domains in complex with RhoA have been determined. We propose that the binding of Ga13 to p115 causes the latter to undergo substantial conformational changes, possibly domain rotation at one or more hinge points. Such conformational changes are required for stimulation of the GEF activity of p115 towards RhoA. We propose to use small angle X-ray scattering to determine the molecular envelope of p115, and that of its complex with Ga13. Atomic-resolution structural models are available for at least 80% of the structural domains that comprise p115, and a structure for the Ga13 has been determined. Understanding the molecular basis by which p115 and its homologs are regulated by G proteins should provide insight into this specific pathway for regulation as well as increase our fundamental understanding of general mechanisms of signaling by G proteins.

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