Redox regulation of Ras and Rho GTPases: mechanism and function.
CONCLUSIONS
Oxidation and reduction events are critical to physiological and pathological processes and are highly regulated. Herein, we present evidence for the role of Ras and Rho GTPases in controlling these events and the unique underlying mechanisms. Evidence for redox regulation of Ras GTPases that contain a redox-sensitive cysteine (X) in the conserved NKXD motif is presented, and a growing consensus supports regulation by a thiyl radical-mediated oxidation mechanism. We also discuss the debate within the literature regarding whether 2e(-) oxidation mechanisms also regulate Ras GTPase activity.


BACKGROUND
We examine the increasing in vitro and cell-based data supporting oxidant-mediated activation of Rho GTPases that contain a redox-sensitive cysteine at the end of the conserved phosphoryl-binding loop (p-loop) motif (GXXXXG[S/T]C). While this motif is distinct from Ras, these data suggest a similar 1e(-) oxidation-mediated activation mechanism.


RESULTS
We also review the data showing that the unique p-loop placement of the redox-sensitive cysteine in Rho GTPases supports activation by 2e(-) cysteine oxidation. Finally, we examine the role that Ras and Rho GTPases play in controlling key oxidant-regulating enzymes in the cell, and we speculate on a feedback mechanism.


CONCLUSIONS
Given that these GTPases and redox-regulating enzymes are involved in multiple physiological and pathological processes, we discuss future experiments that may clarify the interplay between them.
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Lauren
L
Mitchell
G Aaron
GA
Hobbs
Amir
A
Aghajanian
Sharon L
SL
Campbell
D020816:Amino Acid Motifs; D000818:Animals; D020134:Catalytic Domain; D005609:Free Radicals / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006160:Guanosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D019255:NADPH Oxidases / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D011485:Protein Binding; D013482:Superoxide Dismutase / Q000378:metabolism; D018631:ras Proteins / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology
D005609:Free Radicals; D006160:Guanosine Triphosphate; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; D018631:ras Proteins; D020741:rho GTP-Binding Proteins