Structure of the C-terminal guanine nucleotide exchange factor module of Trio in an autoinhibited conformation reveals its oncogenic potential
Abstract
The C-terminal guanine nucleotide exchange factor (GEF) module of Trio (TrioC) transfers signals from the Gαq/11 subfamily of heterotrimeric G proteins to the small guanosine triphosphatase (GTPase) RhoA, enabling Gαq/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 Gαq/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 Gαq/11-independent manner.
- Authors:
-
[1];
[2];
[2];
[2];
[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)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- USDOE Office of Science (SC); National Institutes of Health (NIH); Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor
- OSTI Identifier:
- 1513007
- Grant/Contract Number:
- CA221289; HL122416; HL071818; 5T32GM007767-38; 5T32GM007767-39; F31CA224804; 1U19AI117905; R01GM020501; R01NS070899; R01GM121964; 5T32GM007752-39; AC02-06CH11357; 085P1000817
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Science Signaling
- Additional Journal Information:
- Journal Volume: 12; Journal Issue: 569; Journal ID: ISSN 1945-0877
- Publisher:
- AAAS
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Bandekar, Sumit J., Arang, Nadia, Tully, Ena S., Tang, Brittany A., Barton, Brenna L., Li, Sheng, Gutkind, J. Silvio, and Tesmer, John J. G. Structure of the C-terminal guanine nucleotide exchange factor module of Trio in an autoinhibited conformation reveals its oncogenic potential. United States: N. p., 2019.
Web. doi:10.1126/scisignal.aav2449.
Bandekar, Sumit J., Arang, Nadia, Tully, Ena S., Tang, Brittany A., Barton, Brenna L., Li, Sheng, Gutkind, J. Silvio, & Tesmer, John J. G. Structure of the C-terminal guanine nucleotide exchange factor module of Trio in an autoinhibited conformation reveals its oncogenic potential. United States. https://doi.org/10.1126/scisignal.aav2449
Bandekar, Sumit J., Arang, Nadia, Tully, Ena S., Tang, Brittany A., Barton, Brenna L., Li, Sheng, Gutkind, J. Silvio, and Tesmer, John J. G. Tue .
"Structure of the C-terminal guanine nucleotide exchange factor module of Trio in an autoinhibited conformation reveals its oncogenic potential". United States. https://doi.org/10.1126/scisignal.aav2449. https://www.osti.gov/servlets/purl/1513007.
@article{osti_1513007,
title = {Structure of the C-terminal guanine nucleotide exchange factor module of Trio in an autoinhibited conformation reveals its oncogenic potential},
author = {Bandekar, Sumit J. and Arang, Nadia and Tully, Ena S. and Tang, Brittany A. and Barton, Brenna L. and Li, Sheng and Gutkind, J. Silvio and Tesmer, John J. G.},
abstractNote = {The C-terminal guanine nucleotide exchange factor (GEF) module of Trio (TrioC) transfers signals from the Gαq/11 subfamily of heterotrimeric G proteins to the small guanosine triphosphatase (GTPase) RhoA, enabling Gαq/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 Gαq/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 Gαq/11-independent manner.},
doi = {10.1126/scisignal.aav2449},
journal = {Science Signaling},
number = 569,
volume = 12,
place = {United States},
year = {Tue Feb 19 00:00:00 EST 2019},
month = {Tue Feb 19 00:00:00 EST 2019}
}
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