acompetitivebindingmechanismbetweenskp1and.pdfVIP

THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 286, NO. 22, pp. 19804–19815, June 3, 2011 © 2011 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in the U.S.A. A Competitive Binding Mechanism between Skp1 and Exportin 1 (CRM1) Controls the Localization of a Subset of F-box Proteins* Received for publication, January 12, 2011, and in revised form, March 2, 2011 Published, JBC Papers in Press, March 4, 2011, DOI 10.1074/jbc.M111.220079 David E. Nelson and Heike Laman1 From the Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom SCF-type E3 ubiquitin ligases are crucial regulators of cell into several different subclasses based on their interaction cycle progression. As the F-box protein is the substrate-specify- domains (2, 3). The Fbxw proteins contain WD-40 repeats, and ing subunit of this family of ligases, their availability dictates the Fbxl proteins contain leucine-rich repeats. The remaining FBPs timing and the location of the ubiquitination of substrates. We containing other or unclassified interaction domains are desig- report here our investigation into the regulation of the localiza- nated Fbxo. tion of F-box proteins, in particular Fbxo7, whose mislocaliza- The activity of FBPs can be controlled by restricting them to tion is associated with human disease. We identified a motif in a certain subcellular compartment, bringing them to or Fbxo7 that we have characterized as a functional leucine-rich restricting them from their substrates. This can be achieved by D