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J. Biol. Chem., Vol. 280, Issue 13, 12162-12167, April 1, 2005

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Human Ran Cysteine 112 Oxidation by Pervanadate Regulates Its Binding to Keratins^*

Guo-Zhong Tao, Qin Zhou¶, Pavel Strnad||, Michelle R. Salemi**, Young Moo Lee**, and M. Bishr Omary

From the Palo Alto Veterans Affairs Medical Center, and Stanford University School of Medicine, Palo Alto, California 94304 and the ^**Molecular Structure Facility, University of California, Davis, California 95616

We used a proteomic approach to identify proteins that associate with keratins 8 or 18 (K8/K18) in a pervanadate-dependent manner. Pervanadate triggers Ran-K8/K18 binding and a gel-migration-shift of Ran from 25 to 27 kDa, which does not occur upon exposure to H₂O₂ or vanadate or if pervanadate is excluded during cell solubilization. Generation of 27-kDa Ran is not related to hyperphosphorylation, is heat-insensitive, but occurs upon conversion of Ran cysteines to cysteic acid. The pervanadate-mediated Ran cysteine cysteic acid oxidation and its related gel migration shift affects other proteins including actin. Mutation of the three Ran cysteines (Cys-85, -112, and -120) showed that Ran Cys-112 oxidation generates 27-kDa Ran and accounts for its keratin binding. Proteasome inhibition accentuates Ran-keratin binding after cell exposure to pervanadate. Therefore, cell-free exposure to pervanadate causes cysteine to cysteic acid oxidation of Ran and several other proteins and Ran-K8/K18 association. In cells, stabilization of oxidized Ran by proteasome inhibition promotes Ran-keratin interaction. Keratin sequestration of oxidized Ran may provide a back-up protective mechanism in some cases of oxidative injury.

Received for publication, November 4, 2004 , and in revised form, January 28, 2005.

^* This work is supported in part by National Institutes of Health Grant DK52951 and a Department of Veterans Affairs Merit Award (to M. B. O.) and National Institutes of Health Digestive Disease Center grant DK56339. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains two supplementary tables.

Supported in part by a Crohn's and Colitis Foundation of America Research Award. To whom reprint requests should be addressed: Palo Alto Veterans Affairs Medical Center, Mail code 154J, 3801 Miranda Ave., Palo Alto, CA 94304. Fax: 650-852-3259; E-mail: guozhongtao{at}stanford.edu.

^¶ Supported in part by a Veterans Affairs Research Enhancement Award Program.

^|| Supported by an European Molecular Biology Organization long term post-doctoral fellowship.

To whom correspondence should be addressed: Palo Alto Veterans Affairs Medical Center, Mail code 154J, 3801 Miranda Ave., Palo Alto, CA 94304. Fax: 650-852-3259.

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