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J. Biol. Chem., Vol. 283, Issue 32, 22325-22335, August 8, 2008

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Structure of a Conserved Dimerization Domain within the F-box Protein Fbxo7 and the PI31 Proteasome Inhibitor^*

Rebecca Kirk¹, Heike Laman², Phillip P. Knowles, Judith Murray-Rust, Mikhail Lomonosov³, El Kahina Meziane⁴, and Neil Q. McDonald^¶5

From the Structural Biology Laboratory, London Research Institute, Cancer Research UK, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom, Department of Pathology, University of Cambridge, Tennis Court Rd., Cambridge CB2 1QP, United Kingdom, and ^¶School of Crystallography, Birkbeck College, Malet St., London WC1E 7HX, United Kingdom

F-box proteins are the substrate-recognition components of the Skp1-Cul1-F box protein (SCF) E3 ubiquitin ligases. Here we report a structural relationship between Fbxo7, a component of the SCF^Fbxo7 E3 ligase, and the proteasome inhibitor PI31. SCF^Fbxo7 is known to catalyze the ubiquitination of hepatoma-up-regulated protein (HURP) and the inhibitor of apoptosis (IAP) protein but also functions as an activator of cyclin D-Cdk6 complexes. We identify PI31 as an Fbxo7·Skp1 binding partner and show that this interaction requires an N-terminal domain present in both proteins that we term the FP (Fbxo7/PI31) domain. The crystal structure of the PI31 FP domain reveals a novel /β-fold. Biophysical and mutational analyses are used to map regions of the PI31 FP domain mediating homodimerization and required for heterodimerization with Fbxo7·Skp1. Equivalent mutations in Fbxo7 ablate interaction with PI31 and also block Fbxo7 homodimerization. Knockdown of Fbxo7 does not affect PI31 levels arguing against PI31 being a substrate for SCF^Fbxo7. We present a model for FP domain-mediated dimerization of SCF^Fbxo7 and PI31.

Received for publication, December 4, 2007 , and in revised form, May 12, 2008.

The atomic coordinates and structure factors (code 2VT8) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* 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 Recipient of a Barbara Mary Hill Fellowship from Cancer Research UK. Current address: Research Institute of Molecular Pathology, 1030 Vienna, Austria.

³ Funded by Cancer Research UK.

⁴ Funded by Association for International Cancer Research.

² To whom correspondence may be addressed. Tel.: 44-1223-333-722; E-mail: hl316{at}cam.ac.uk.

⁵ To whom correspondence may be addressed. Tel.: 44-207-269-3259; E-mail: neil.mcdonald{at}cancer.org.uk.

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