Structure of the C-terminal guanine nucleotide exchange factor module of Trio in an autoinhibited conformation reveals its oncogenic potential

Bandekar, Sumit J.; Arang, Nadia; Tully, Ena S.; Tang, Brittany A.; Barton, Brenna L.; Li, Sheng; Gutkind, J. Silvio; Tesmer, John J.  G.

doi:10.1126/scisignal.aav2449

Title: Structure of the C-terminal guanine nucleotide exchange factor module of Trio in an autoinhibited conformation reveals its oncogenic potential

Journal Article · Tue Feb 19 00:00:00 EST 2019 · Science Signaling

DOI:https://doi.org/10.1126/scisignal.aav2449· OSTI ID:1513007

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^[2]; Tully, Ena S. ^[1]; Tang, Brittany A. ^[1]; Barton, Brenna L. ^[1];

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^[3]

Univ. of Michigan, Ann Arbor, MI (United States)
Univ. of California, San Diego, La Jolla, CA (United States)
Purdue Univ., West Lafayette, IN (United States)

The C-terminal guanine nucleotide exchange factor (GEF) module of Trio (TrioC) transfers signals from the Gα_q/11 subfamily of heterotrimeric G proteins to the small guanosine triphosphatase (GTPase) RhoA, enabling Gα_q/11-coupled G protein–coupled receptors (GPCRs) to control downstream events, such as cell motility and gene transcription. This conserved signal transduction axis is crucial for tumor growth in uveal melanoma. Prior studies indicate that the GEF activity of the TrioC module is autoinhibited, with release of autoinhibition upon Gα_q/11 binding. Here, we determined the crystal structure of TrioC in its basal state and found that the pleckstrin homology (PH) domain interacts with the Dbl homology (DH) domain in a manner that occludes the Rho GTPase binding site, thereby suggesting the molecular basis of TrioC autoinhibition. Biochemical and biophysical assays revealed that disruption of the autoinhibited conformation destabilized and activated the TrioC module in vitro. Last, mutations in the DH-PH interface found in patients with cancer activated TrioC and, in the context of full-length Trio, led to increased abundance of guanosine triphosphate–bound RhoA (RhoA·GTP) in human cells. These mutations increase mitogenic signaling through the RhoA axis and, therefore, may represent cancer drivers operating in a Gα_q/11-independent manner.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC); National Institutes of Health (NIH); Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor

Grant/Contract Number:: CA221289; HL122416; HL071818; 5T32GM007767-38; 5T32GM007767-39; F31CA224804; 1U19AI117905; R01GM020501; R01NS070899; R01GM121964; 5T32GM007752-39; AC02-06CH11357; 085P1000817

OSTI ID:: 1513007

Journal Information:: Science Signaling, Vol. 12, Issue 569; ISSN 1945-0877

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 15 works

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