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Molecular and Cellular Biology, September 2008, p. 5555-5568, Vol. 28, No. 18
0270-7306/08/$08.00+0     doi:10.1128/MCB.00524-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

A Unique Protection Signal in Cubitus interruptus Prevents Its Complete Proteasomal Degradation{triangledown} ,{dagger}

Yifei Wang1 and Mary Ann Price2*

Department of Biomedical Sciences, University of Sheffield, Sheffield S10 2TN, United Kingdom,1 Okinawa Institute of Science and Technology, Okinawa 904-2234, Japan2

Received 1 April 2008/ Returned for modification 30 April 2008/ Accepted 2 July 2008

The limited proteolysis of Cubitus interruptus (Ci), the transcription factor for the developmentally and medically important Hedgehog (Hh) signaling pathway, triggers a critical switch between transcriptional repressor and activator forms. Ci repressor is formed when the C terminus of full-length Ci is degraded by the ubiquitin-proteasome pathway, an unusual reaction since the proteasome typically completely degrades its substrates. We show that several regions of Ci are required for generation of the repressor form: the zinc finger DNA binding domain, a single lysine residue (K750) near the degradation end point, and a 163-amino-acid region at the C terminus. Unlike other proteins that are partially degraded by the proteasome, dimerization is not a key feature of Ci processing. Using a pulse-chase assay in cultured Drosophila cells, we distinguish between regions required for initiation of degradation and those required for the protection of the Ci N terminus from degradation. We present a model whereby the zinc finger region and K750 together form a unique protection signal that prevents the complete degradation of Ci by the proteasome.

* Corresponding author. Mailing address: Okinawa Institute of Science and Technology, 12-22 Suzaki, Uruma-shi, Okinawa 904-2234, Japan. Phone: 81 98 929 1305. Fax: 81 98 929 0596. E-mail: m.a.price{at}oist.jp

{triangledown} Published ahead of print on 14 July 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, September 2008, p. 5555-5568, Vol. 28, No. 18
0270-7306/08/$08.00+0     doi:10.1128/MCB.00524-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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