Crystal Structure of the C‐terminal Guanine Exchange Factor Module of Trio Reveals its Oncogenic Potential
- Medicinal Chemistry University of Michigan Ann Arbor MI
- Biomedical Sciences University of California San Diego La Jolla CA
- University of Michigan Ann Arbor MI
- Medicine University of California San Diego La Jolla CA
- Pharmacology University of California San Diego La Jolla CA
- Biological sciences Purdue University West lafayette IN
The C‐terminal guanine exchange factor module of Trio (TrioC) activates the small G protein RhoA, linking Gα q/11 ‐coupled 7TM receptors to cellular events including cytoskeletal rearrangements and gene transcription. This signal transduction pathway underlies the development of uveal melanoma, a fatal malignancy. Previous studies have shown that TrioC is regulated via autoinhibition relieved by the binding of Gα q/11 . However, the structural determinants of the autoinhibited state have remained elusive. We determined the crystal structure of TrioC in its basal state, revealing the molecular basis of autoinhibition mediated by the pleckstrin homology (PH) domain via direct interactions with the Rho binding site on the Dbl homology domain (DH). We show that truncation of the PH domain or introduction of point mutations activates the TrioC module in nucleotide exchange assays by liberating the Rho binding site. This model is consistent with results obtained by hydrogen‐deuterium exchange mass spectrometry. Finally, we show that mutations in the PH domain found in cancer patients also hyper‐activate full length TrioC in cell based models. These mutations may thus represent the first known cancer drivers in Trio that operate in an analogous, yet Gα q/11 ‐independent manner. Support or Funding Information This work was supported by NIH Grants CA221289, HL122416, and HL071818 (to J.J.G.T.), 5T32GM007767‐38, 5T32GM007767‐39, and F31CA224804 (to S.J.B.), and 5T32GM007752‐39 (to N.A.). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE‐AC02‐06CH11357. Use of the LS‐CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri‐Corridor (Grant 085P1000817). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
- Sponsoring Organization:
- USDOE
- OSTI ID:
- 1786663
- Journal Information:
- FASEB Journal, Journal Name: FASEB Journal Vol. 33 Journal Issue: S1; ISSN 0892-6638
- Publisher:
- FASEBCopyright Statement
- Country of Publication:
- United States
- Language:
- English
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