6D8Z

Crystal Structure of the C-terminal Guanine Nucleotide Exchange Factor Module of Human Trio

Summary for 6D8Z

• Entry DOI: 10.2210/pdb6d8z/pdb
• Descriptor: Triple functional domain protein (2 entities in total)
• Functional Keywords: rhogef, dbl family member, dbl homology, pleckstrin homology, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 3
• Total formula weight: 112446.82

Authors

Bandekar, S.,Tesmer, J.J. (deposition date: 2018-04-27, release date: 2019-02-20, Last modification date: 2023-10-04)

Primary citation

Bandekar, S.J.,Arang, N.,Tully, E.S.,Tang, B.A.,Barton, B.L.,Li, S.,Gutkind, J.S.,Tesmer, J.J.G.
Structure of the C-terminal guanine nucleotide exchange factor module of Trio in an autoinhibited conformation reveals its oncogenic potential.
Sci Signal, 12:-, 2019

PubMed Abstract: The C-terminal guanine nucleotide exchange factor (GEF) module of Trio (TrioC) transfers signals from the Gα subfamily of heterotrimeric G proteins to the small guanosine triphosphatase (GTPase) RhoA, enabling Gα-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. Previous studies indicate that the GEF activity of the TrioC module is autoinhibited, with release of autoinhibition upon Gα 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-independent manner.

PubMed: 30783010
DOI: 10.1126/scisignal.aav2449

Experimental method

X-RAY DIFFRACTION (2.65 Å)