Cysteine regulation of protein function--as exemplified by NMDA-receptor modulation.
Until recently cysteine residues, especially those located extracellularly, were thought to be important for metal coordination, catalysis and protein structure by forming disulfide bonds - but they were not thought to regulate protein function. However, this is not the case. Crucial cysteine residues can be involved in modulation of protein activity and signaling events via other reactions of their thiol (sulfhydryl; -SH) groups. These reactions can take several forms, such as redox events (chemical reduction or oxidation), chelation of transition metals (chiefly Zn(2+), Mn(2+) and Cu(2+)) or S-nitrosylation [the catalyzed transfer of a nitric oxide (NO) group to a thiol group]. In several cases, these disparate reactions can compete with one another for the same thiol group on a single cysteine residue, forming a molecular switch composed of a latticework of possible redox, NO or Zn(2+) modifications to control protein function. Thiol-mediated regulation of protein function can also involve reactions of cysteine residues that affect ligand binding allosterically. This article reviews the basis for these molecular cysteine switches, drawing on the NMDA receptor as an exemplary protein, and proposes a molecular model for the action of S-nitrosylation based on recently derived crystal structures.
Center for Neuroscience and Aging, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. slipton@burnham.org
Stuart A
SA
Lipton
Yun-Beom
YB
Choi
Hiroto
H
Takahashi
Dongxian
D
Zhang
Weizhong
W
Li
Adam
A
Godzik
Laurie A
LA
Bankston
D000818:Animals; D003545:Cysteine / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D009569:Nitric Oxide / Q000378:metabolism; D010084:Oxidation-Reduction; D017434:Protein Structure, Tertiary; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000502:physiology*; D026403:S-Nitrosothiols / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism
D016194:Receptors, N-Methyl-D-Aspartate; D026403:S-Nitrosothiols; D013438:Sulfhydryl Compounds; D009569:Nitric Oxide; D003545:Cysteine