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J. Biol. Chem., Vol. 282, Issue 41, 29936-29945, October 12, 2007

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Substrate Modification with Lysine 63-linked Ubiquitin Chains through the UBC13-UEV1A Ubiquitin-conjugating Enzyme^*

From the Rigel Pharmaceuticals, Inc., South San Francisco, California 94080

Protein modification with lysine 63-linked ubiquitin chains has been implicated in the non-proteolytic regulation of signaling pathways. To understand the molecular mechanisms underlying this process, we have developed an in vitro system to examine the activity of the ubiquitin-conjugating enzyme UBC13-UEV1A with TRAF6 in which TRAF6 serves as both a ubiquitin ligase and substrate for modification. Although TRAF6 potently stimulates the activity of UBC13-UEV1A to synthesize ubiquitin chains, it is not appreciably ubiquitinated. We have determined that the presentation of Lys⁶³ of ubiquitin by UEV1A suppresses TRAF6 modification. Based on our observations, we propose that the modification of proteins with Lys⁶³-linked ubiquitin chains occurs through a UEV1A-independent substrate modification and UEV1A-dependent Lys⁶³-linked ubiquitin chain synthesis mechanism.

Received for publication, May 11, 2007 , and in revised form, July 24, 2007.

^* 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.

¹ To whom correspondence should be addressed. Present address: Burnham Institute for Medical Research, 10901 North Torrey Pines Rd., La Jolla, CA 92037. Fax: 858-795-5298; E-mail: matt.petroski{at}yahoo.com.

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