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J. Biol. Chem., Vol. 282, Issue 15, 10846-10852, April 13, 2007

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A Novel Protein-processing Domain in Gli2 and Gli3 Differentially Blocks Complete Protein Degradation by the Proteasome^*

Yong Pan and Baolin Wang¹

From the Department of Genetic Medicine and Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, New York 10021

The proteasome usually completely degrades its target proteins, but it can also degrade a handful of proteins in a limited and site-specific manner. The molecular mechanism for such limited degradation is unknown. The repressor forms of Gli2 and Gli3 transcription factors are generated from their full-length proteins through limited proteasome-mediated protein degradation. In this study, we have taken advantage of the fact that Gli3 is efficiently processed, whereas Gli2 is not, and identified a region of 200 residues in their C termini that determine differential processing of the two proteins. This region, named processing determinant domain, functions as a signal for protein processing in the context of not only Gli2 and Gli3 protein sequences but also a heterologous hybrid protein, which would otherwise be completely degraded by the proteasome. Thus, the processing determinant domain constitutes a novel domain that functions independently. Our findings explain, at the molecular level, why Gli2 and Gli3 are differentially processed and, more importantly, may help understand a probably general mechanism by which the proteasome degrades some of its target proteins partially rather than completely.

Received for publication, September 6, 2006 , and in revised form, January 23, 2007.

^* This work was supported by National Institutes of Health Grant R01 GM70820 (to B. W.). 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: Dept. of Genetic Medicine, Weill Medical College of Cornell University, 1300 York Ave., W404, New York, NY 10021. Tel.: 212-746-5357; Fax: 212-746-8318; E-mail: baw2001{at}med.cornell.edu.

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