PUBLICATION
Structural basis of the specificity of USP18 toward ISG15
- Authors
- Basters, A., Geurink, P.P., Röcker, A., Witting, K.F., Tadayon, R., Hess, S., Semrau, M.S., Storici, P., Ovaa, H., Knobeloch, K.P., Fritz, G.
- ID
- ZDB-PUB-170622-16
- Date
- 2017
- Source
- Nature structural & molecular biology 24: 270-278 (Journal)
- Registered Authors
- Keywords
- Immunology, Proteases, Ubiquitylation, X-ray crystallography
- MeSH Terms
-
- Protein Domains
- Crystallization
- Cytokines/chemistry
- Cytokines/metabolism*
- Protein Binding
- HEK293 Cells
- Humans
- Endopeptidases/chemistry*
- Endopeptidases/metabolism
- Substrate Specificity
- Mutant Proteins/chemistry
- Mutant Proteins/metabolism
- Zebrafish
- Hydrophobic and Hydrophilic Interactions
- Models, Molecular
- Ubiquitin/metabolism
- Animals
- Kinetics
- Ubiquitins/chemistry
- Ubiquitins/metabolism
- Crystallography, X-Ray
- Ubiquitin Thiolesterase/chemistry*
- Ubiquitin Thiolesterase/metabolism*
- Structure-Activity Relationship
- Protein Conformation
- Zebrafish Proteins/chemistry*
- Zebrafish Proteins/metabolism
- PubMed
- 28165509 Full text @ Nat. Struct. Mol. Biol.
Citation
Basters, A., Geurink, P.P., Röcker, A., Witting, K.F., Tadayon, R., Hess, S., Semrau, M.S., Storici, P., Ovaa, H., Knobeloch, K.P., Fritz, G. (2017) Structural basis of the specificity of USP18 toward ISG15. Nature structural & molecular biology. 24:270-278.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping