6d8z | pdb_00006d8z

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

spinqualitylabelsall models 6d8z, resolution 2.65Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6d8z is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Gene: TRIO (HUMAN) Activity: Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [TRIO_HUMAN] Promotes the exchange of GDP by GTP. Together with leukocyte antigen-related (LAR) protein, it could play a role in coordinating cell-matrix and cytoskeletal rearrangements necessary for cell migration and cell growth. Publication Abstract from PubMed The C-terminal guanine nucleotide exchange factor (GEF) module of Trio (TrioC) transfers signals from the Galphaq/11 subfamily of heterotrimeric G proteins to the small guanosine triphosphatase (GTPase) RhoA, enabling Galphaq/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. Previous studies indicate that the GEF activity of the TrioC module is autoinhibited, with release of autoinhibition upon Galphaq/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 Galphaq/11-independent manner. Structure of the C-terminal guanine nucleotide exchange factor module of Trio in an autoinhibited conformation reveals its oncogenic potential.,Bandekar SJ, Arang N, Tully ES, Tang BA, Barton BL, Li S, Gutkind JS, Tesmer JJG Sci Signal. 2019 Feb 19;12(569). pii: 12/569/eaav2449. doi:, 10.1126/scisignal.aav2449. PMID:30783010 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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