title: Redox-regulated conformational changes in an SH3 domain.
abstract: Oxidation-induced conformational changes in proteins provide a powerful mechanism to sense the redox state of a living cell. In contrast to the unspecific and often irreversible oxidation of intracellular proteins during severe oxidative stress, regulatory redox events need to have specific and transient effects on cellular targets. Here we present evidence for the reversible formation of a vicinal disulfide bond in a prototypic protein interaction domain. NMR spectroscopy was used to determine the structure of the N-terminal hSH3 domain (hSH3N) of the immune cell protein ADAP (adhesion and degranulation promoting adapter protein) in the reduced and oxidized states. An eight-membered ring formed upon oxidation of two neighboring cysteines leads to significant changes in the variable arginine-threonine (RT) loop of the hSH3N domain and alters the helix-sheet packing of the domain. The redox potential for this structural transition is -228 mV at pH 7.4. This is compatible with a role of the cysteinylcysteine moiety in redox signaling during T cell activation.
authors.affiliation: Protein Engineering Group, Leibniz-Institut für Molekulare Pharmakologie und Freie Universität Berlin, 13125 Berlin, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Zimmermann
authors.forename: Ronald
authors.initials: R
authors.lastname: Kühne
authors.forename: Marc
authors.initials: M
authors.lastname: Sylvester
authors.forename: Christian
authors.initials: C
authors.lastname: Freund
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000378:metabolism*; D003001:Cloning, Molecular; D006801:Humans; D008213:Lymphocyte Activation; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010084:Oxidation-Reduction; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C106957:FYB1 protein, human; D011994:Recombinant Proteins