Abstract
The C‐terminal Guanine Exchange Factor (GEF) domain of the RhoGEF Trio (TrioC) has recently been implicated in highly metastatic cancers including uveal melanoma and adult T‐cell leukemia. Upon aberrant activation, TrioC transduces growth and motility signals through the small GTPase RhoA. The regulation of TrioC is not understood on a molecular level and this presents a barrier to future inhibitor design efforts. Preliminary biochemical studies have shown that TrioC is regulated via an autoinhibitory constraint that is released upon the binding of the heterotrimeric G‐protein Gαq. I have solved the 2.7Å crystal structure of TrioC in its basal state, revealing high‐resolution detail of the autoinhibition mechanism. Analysis of this structure in comparison to the activated state of a closely related protein, p63RhoGEF reveals a dramatically different orientation of key regulatory regions. Mutational analysis of these regulatory regions are underway using FRET‐based activity assays and differential scanning fluorimetry. Analysis of current data supports that residues in the α6‐αN linker helix and β3‐β4 loop regions are indeed responsible for stabilizing the autoinhibited state of TrioC. A Trio inhibitory peptide (TRIPα) represents the only known inhibitor of TrioC. I have expressed the peptide as an MBP fusion and am attempting to determine a co‐crystal structure of TRIPα in complex with TrioC.Support or Funding Information5T32GM007767‐38, Rackham pre‐doctoral fellowship awarded to S. Bandekar UROP Summer fellowship awarded to B. Barton
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