Structural determinants of rgs-rhogef signaling critical to entamoeba histolytica pathogenesis

Dustin E. Bosch, Adam J. Kimple, Alyssa J. Manning, Robin E. Muller, Francis S. Willard, Mischa MacHius, Stephen L. Rogers, David P. Siderovski

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

G protein signaling pathways, as key components of physiologic responsiveness and timing, are frequent targets for pharmacologic intervention. Here, we identify an effector for heterotrimeric G protein α subunit (EhGα1) signaling from Entamoeba histolytica, the causative agent of amoebic colitis. EhGα1 interacts with this effector and guanosine triphosphatase-accelerating protein, EhRGS-RhoGEF, in a nucleotide state-selective fashion. Coexpression of EhRGS-RhoGEF with constitutively active EhGα1 and EhRacC leads to Rac-dependent spreading in Drosophila S2 cells. EhRGS-RhoGEF overexpression in E. histolytica trophozoites leads to reduced migration toward serum and lower cysteine protease activity, as well as reduced attachment to, and killing of, host cells. A 2.3 Å crystal structure of the full-length EhRGS-RhoGEF reveals a putative inhibitory helix engaging the Dbl homology domain Rho-binding surface and the pleckstrin homology domain. Mutational analysis of the EhGα1/EhRGS-RhoGEF interface confirms a canonical "regulator of G protein signaling" domain rather than a RhoGEF-RGS ("rgRGS") domain, suggesting a convergent evolution toward heterotrimeric and small G protein cross-talk.

Original languageEnglish
Pages (from-to)65-75
Number of pages11
JournalStructure
Volume21
Issue number1
DOIs
StatePublished - 8 Jan 2013

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    Bosch, D. E., Kimple, A. J., Manning, A. J., Muller, R. E., Willard, F. S., MacHius, M., Rogers, S. L., & Siderovski, D. P. (2013). Structural determinants of rgs-rhogef signaling critical to entamoeba histolytica pathogenesis. Structure, 21(1), 65-75. https://doi.org/10.1016/j.str.2012.11.012