Atypical Rho Family Members

Abstract

Of the 20 Rho GTP-binding proteins in humans, 8 have atypical properties, which are also unusual within the Ras superfamily. These atypical proteins fall into four subfamilies: RhoU/RhoV, Rnd1/Rnd2/Rnd3, RhoH and RhoBTB1/ RhoBTB2. These proteins are known or predicted to be predominantly GTP-bound in cells, because of changes in their ability to exchange GDP for GTP or to hydrolyse GTP. Apart from RhoH, they also have N-terminal and C-terminal extensions that give them unique interacting partners and functions. For example, RhoU can bind SH3 domain-containing proteins, Rnd proteins can bind to 14-3-3 proteins, and RhoBTB proteins can interact via their BTB domains with cullin-3, which is involved in proteasomal degradation. The proteins have been implicated in diverse functions, including cell adhesion and migration, vesicle trafficking and cell proliferation.

Structural Mechanisms and Drug Discovery Prospects of Rho GTPases

“…The human genome encodes 22 Rho family members [ 3 ] with RhoA, Cdc42, and Rac1 being the best characterized and exemplifying the key functional features ( Figure 1 ). With the exception of eight atypical Rho family members that either bind GTP constitutively (Rnd1, Rnd2, Rnd3, RhoH, RhoU, and RhoV), or are predicted to not bind GTP (RhoBTB1, and RhoBTB) [ 6 ], most Rho GTPases are molecular switches which hydrolyze GTP [ 7 ]. The various family members are involved in signal transduction pathways that regulate cellular proliferation, apoptosis, polarity, adhesion [ 1 ], motility [ 8 ], and cytoskeletal organization [ 9 ].…”

“…The atypical RhoBTB and RhoBTB2 relatives contain two long form BTB domains [ 30 ]. The first BTB is split by a 115 residue insertion [ 6 ], which forms a loop of unknown function. BTB domains mediate protein-protein interactions [ 31 ], frequently facilitating the formation of homodimeric [ 30 ], heterodimeric [ 32 ], and occasionally higher order oligomers [ 31 ].…”