Light on the structural communication in Ras GTPases

Abstract

The graph theory was combined with fluctuation dynamics to investigate the structural communication in four small G proteins, Arf1, H-Ras, RhoA, and Sec4. The topology of small GTPases is such that it requires the presence of the nucleotide to acquire a persistent structural network. The majority of communication paths involves the nucleotide and does not exist in the unbound forms. The latter are almost devoid of high-frequency paths. Thus, small Ras GTPases acquire the ability to transfer signals in the presence of nucleotide, suggesting that it modifies the intrinsic dynamics of the protein through the establishment of regions of hyperlinked nodes with high occurrence of correlated motions. The analysis of communication paths in the inactive (SGDP) and active (SGTP) states of the four G proteins strengthened the separation of the Ras-like domain into two dynamically distinct lobes, i.e. lobes 1 and 2, representing, respectively, the N-terminal and C-terminal halves of the domain. In the framework of this separation, interfunctional states and interfamily differences could be inferred. The structure network undergoes a reshaping depending on the bound nucleotide. Nucleotide-dependent divergences in structural communication reach the maximum in Arf1 and the minimum in RhoA. In Arf1, the nucleotide-dependent paths essentially express a communication between the G box 4 (G4) and distal portions of lobe 1. In the SGDP state, the G4 communicates with the N-term, while, in the SGTP state, the G4 communicates with the switch II. Clear differences could be also found between Arf1 and the other three G proteins. In Arf1, the nucleotide tends to communicate with distal portions of lobe 1, whereas in H-Ras, RhoA, and Sec4 it tends to communicate with a cluster of aromatic/hydrophobic amino acids in lobe 2. These differences may be linked, at least in part, to the divergent membrane anchoring modes that would involve the N-term for the Arf family and the C-term for the Rab/Ras/Rho families.