Structural/functional studies of Trio provide insights into its configuration and show that conserved linker elements enhance its activity for Rac1

New Mechanisms Underlying Oncogenesis in Dbl Family Rho Guanine Nucleotide Exchange Factors

“…The CT domain belongs to the SEC14 family, which are known to bind phosphoinositides, and a single report suggests that it could be a binding site for G (Nishida et al, 1999), implying that it could serve as a membrane targeting module. Negative stain EM of the N terminal region of Trio (61-1594aa) encompassing all nine spectrin repeats and TrioN revealed the fragment to be highly extended (Bandekar et al, 2022), suggesting that the spectrin repeats may serve to maintain distance between the membrane binding domain (CT) and TrioN module, which is somehow critical for neurite outgrowth (Xu et al, 2013). The PH domain of TrioN plays a positive regulatory role by directly binding to bound GTPases, and hence the DH/PH module has ~ 4 fold more GEF activity than the isolated DH domain (Chhatriwala et al, 2007).…”

“…The PH domain of TrioN plays a positive regulatory role by directly binding to bound GTPases, and hence the DH/PH module has ~ 4 fold more GEF activity than the isolated DH domain (Chhatriwala et al, 2007). The SH3 domain immediately downstream of the TrioN module, along with the 200 amino acid low complexity linker following it, also potentiates nucleotide exchange of TrioN on Rac by ~2.5-3 fold over TrioN alone, however, due to the intrinsic flexibility of this region, a mechanism of activation has not be determined (Bandekar et al, 2022). A recent study suggested that spectrin repeats (6-9) can negatively regulate TrioN GEF activity via direct interactions with the PH domain (Fig.…”