1. Center for Integrated Protein Science at the Department Chemie, Lehrstuhl für Biochemie, Technische Universität München, Lichtenbergstrasse 4, D-85747 Garching, Germany
2. Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, USA
3. Institute for Biochemistry II and Cluster of Excellence Macromolecular Complexes, Goethe University, Theodor-Stern-Kai 7, D-60590 Frankfurt (Main), Germany
4. Tumor Biology Program, Mediterranean Institute for Life Sciences, Mestrovicevo setaliste, 21000 Split, Croatia
5. Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA
6. Department of Immunology, Medical School University of Split, Soltanska 2, 21000 Split, Croatia
7. Institute of Biochemistry, Charité-Universitatsmedizin Berlin CCM, Monbijoustrae 2, D-10117 Berlin, Germany
8. These authors contributed equally to this work.

Correspondence to: Ivan Dikic^3,4,6Kylie J. Walters²Michael Groll^1,7 Correspondence and requests for materials should be addressed to M.G. (Email: michael.groll@ch.tum.de), K.J.W. (Email: walte048@umn.edu) or I.D. (Email: ivan.dikic@biochem2.de).

Abstract

Targeted protein degradation is largely performed by the ubiquitin–proteasome pathway, in which substrate proteins are marked by covalently attached ubiquitin chains that mediate recognition by the proteasome. It is currently unclear how the proteasome recognizes its substrates, as the only established ubiquitin receptor intrinsic to the proteasome is Rpn10/S5a (ref. 1), which is not essential for ubiquitin-mediated protein degradation in budding yeast². In the accompanying manuscript we report that Rpn13 (refs 3–7), a component of the nine-subunit proteasome base, functions as a ubiquitin receptor⁸, complementing its known role in docking de-ubiquitinating enzyme Uch37/UCHL5 (refs 4–6) to the proteasome. Here we merge crystallography and NMR data to describe the ubiquitin-binding mechanism of Rpn13. We determine the structure of Rpn13 alone and complexed with ubiquitin. The co-complex reveals a novel ubiquitin-binding mode in which loops rather than secondary structural elements are used to capture ubiquitin. Further support for the role of Rpn13 as a proteasomal ubiquitin receptor is demonstrated by its ability to bind ubiquitin and proteasome subunit Rpn2/S1 simultaneously. Finally, we provide a model structure of Rpn13 complexed to diubiquitin, which provides insights into how Rpn13 as a ubiquitin receptor is coupled to substrate deubiquitination by Uch37.

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