Structural basis of the specificity of USP18 toward ISG15

DOI: 10.1038/nsmb.3371

Authors: Anja Basters (Friedrich Miescher Institute for Biomedical Research; Institute of Neuropathology, Faculty of Medicine, University of Freiburg) , Paul P Geurink (Department of Chemical Immunology, Leiden University Medical Center) , Annika Röcker (Institute of Neuropathology, Faculty of Medicine, University of Freiburg) , Katharina F Witting (Department of Chemical Immunology, Leiden University Medical Center) , Roya Tadayon (Hermann-Staudinger Graduate School, University of Freiburg) , Sandra Hess (Institute of Neuropathology, Faculty of Medicine, University of Freiburg) , Marta S Semrau (Structural Biology Laboratory, Elettra Sincrotrone Trieste S.C.p.A.) , Paola Storici (Structural Biology Laboratory, Elettra Sincrotrone Trieste S.C.p.A.) , Huib Ovaa (Department of Chemical Immunology, Leiden University Medical Center) , Klaus-Peter Knobeloch (Institute of Neuropathology, Faculty of Medicine, University of Freiburg) , Günter Fritz (Institute of Neuropathology, Faculty of Medicine, University of Freiburg)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Structural & Molecular Biology

State: Published (Approved)
Published: February 2017
Diamond Proposal Number(s): 9694 , 12090

Abstract: Protein modification by ubiquitin and ubiquitin-like modifiers (Ubls) is counteracted by ubiquitin proteases and Ubl proteases, collectively termed DUBs. In contrast to other proteases of the ubiquitin-specific protease (USP) family, USP18 shows no reactivity toward ubiquitin but specifically deconjugates the interferon-induced Ubl ISG15. To identify the molecular determinants of this specificity, we solved the crystal structures of mouse USP18 alone and in complex with mouse ISG15. USP18 was crystallized in an open and a closed conformation, thus revealing high flexibility of the enzyme. Structural data, biochemical and mutational analysis showed that only the C-terminal ubiquitin-like domain of ISG15 is recognized and essential for USP18 activity. A critical hydrophobic patch in USP18 interacts with a hydrophobic region unique to ISG15, thus providing evidence that USP18's ISG15 specificity is mediated by a small interaction interface. Our results may provide a structural basis for the development of new drugs modulating ISG15 linkage.

Journal Keywords: Immunology; Proteases; Ubiquitylation; X-ray crystallography

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Other Facilities: Swiss Light Source

Added On: 13/02/2017 15:30

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)