Water in Ras Superfamily Evolution

Abstract

The Ras GTPase superfamily of proteins coordinates a diverse set of cellular outcomes, including cell morphology, vesicle transport, and cell proliferation. Primary amino acid sequence analysis has identified Specificity determinant positions (SDPs) that drive diversified functions specific to the Ras, Rho, Rab, and Arf subfamilies (Rojas et al. 2012, J Cell Biol 196:189–201). The inclusion of water molecules in structural and functional adaptation is likely to be a major response to the selection pressures that drive evolution, yet hydration patterns are not included in phylogenetic analysis. This article shows that conserved crystallographic water molecules coevolved with SDP residues in the differentiation of proteins within the Ras superfamily of small GTPases. The patterns of water conservation between protein subfamilies parallel those of sequence‐based evolutionary trees. Thus, hydration patterns have the potential to help elucidate functional significance in the evolution of amino acid residues observed in phylogenetic analysis of homologous proteins. © 2019 Wiley Periodicals, Inc.

Equilibria between conformational states of the Ras oncogene protein revealed by high pressure crystallography

“…This reflects the hydration of the proteins by pressure, 3,6,8 as similarly observed in many high pressure crystal structures, 46–48 and may probably participate to the water-mediated allosteric interactions. 33 …”

“…This reflects the hydration of the proteins by pressure, 3,6,8 as similarly observed in many high pressure crystal structures, [46][47][48] and may probably participate to the watermediated allosteric interactions. 33 In all structures of Ras(wt) and Ras(D33K) under pressure, there is almost no structural modification in the P-loop which tightly binds to the phosphate groups and contains the crucial Lys 16 and Ser 17 residues, as well as in the G4 and G5 motifs, both connected to the purine moiety of the nucleotide. The intrinsic rigidity of these regions, revealed by pressure, is therefore directly connected to the Ras cycling efficiency.…”

“…In the state 2(T), an allosteric network has been described between the effector lobe, containing the active site and the effector binding regions, and the C-terminal allosteric lobe, containing the membrane interacting regions, through many direct and water-mediated connections. 25,26,[33][34][35] This allosteric network regulates the interaction of Ras with effectors, with a transition between two states 2(T), termed "on" and "off". In the "on" state, the allosteric switch (composed of the 3 helix and the loop 5) is shifted toward the 4 helix and the switch II is ordered with the residue Gln 61 ready for catalysis, while in the "off" state, the allosteric switch is shifted toward the switch II, inducing the disorganization of its N-terminal portion.…”

Dynamically encoded reactivity of Ras enzymes: opening new frontiers for drug discovery

“…The analysis also indicated that the switch regions are connected, with switch II driving the motion of switch I [49]. Conserved water molecules were also shown to be an integral part of Ras structure and catalysis [50,51].…”

Identification, classification and expression analysis of the Ras superfamily genes in the Pacific white shrimp, Litopenaeus vannamei

“…superfamily to be discovered, and then Ran, Rho, Rab, Arf and other families (Marcus and Mattos, 2020). They control different signal transduction pathways in cells, including proliferation, differentiation, morphology, polarity, adhesion, migration, survival, apoptosis, etc.…”