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Crystal Structure of the C‐terminal Guanine Exchange Factor Module of Trio Reveals its Oncogenic Potential
Author(s) -
Bandekar Sumit
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.557.2
Subject(s) - heterotrimeric g protein , guanine nucleotide exchange factor , rhoa , pleckstrin homology domain , point mutation , g protein , guanine , signal transduction , chemistry , gene , biology , mutant , microbiology and biotechnology , genetics , nucleotide
The C‐terminal guanine exchange factor module of Trio (TrioC) serves as a link between the heterotrimeric G proteins Gα q/11 and the small G‐protein RhoA, joining Gα q/11 ‐coupled GPCRs to downstream events of cell motility and gene transcription. This ancient signal transduction axis has been identified as crucial to the rise and spread of the fatal malignancy uveal melanoma. Previous studies have shown that TrioC is likely regulated via an autoinhibitory constraint that is released upon binding of Gα q/11 . However, the structural determinants of this autoinhibition remain unclear. We have determined the crystal structure of TrioC in its basal state, revealing high‐resolution detail of autoinhibition mediated by the Pleckstrin Homology (PH) domain. We show that truncation of the PH domain activates the module in vitro, showcasing the importance of the αN helix found at the DH/PH junction. We then show using two orthogonal biochemical assays that the disruption of the autoinhibited conformation by point mutations destabilizes and activates the module. Finally, we show that mutations in αN found in cancer patients hyperactivate TrioC. These point mutations likely increase mitogenic signaling through the RhoA axis and may thus represent the first known cancer drivers identified in Trio, operating in an analogous, yet Gα q/11 independent manner. We are in the process of confirming this hypothesis using cell‐based assays. Support or Funding Information Rackham Graduate Student Research Grant, University of Michigan Horace H. Rackham Graduate School Pharmacological Sciences Training Program Fellow, 5T32GM007767–38 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .