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Structural basis of the specificity of USP18 toward ISG15
- Source :
- Nature structural & molecular biology, Nature Structural & Molecular Biology, Nature Structural and Molecular Biology, 24(3), 270
- Publication Year :
- 2017
-
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.
- Subjects :
- 0301 basic medicine
Models, Molecular
Proteases
Protein Conformation
medicine.medical_treatment
Protein domain
Plasma protein binding
Bioinformatics
Crystallography, X-Ray
Article
Substrate Specificity
03 medical and health sciences
Structure-Activity Relationship
Protein structure
Ubiquitin
Protein Domains
Structural Biology
Hydrolase
Endopeptidases
medicine
Animals
Humans
Molecular Biology
Ubiquitins
Zebrafish
Protease
030102 biochemistry & molecular biology
biology
Zebrafish Proteins
ISG15
Cell biology
Kinetics
030104 developmental biology
HEK293 Cells
biology.protein
Cytokines
Mutant Proteins
Crystallization
Hydrophobic and Hydrophilic Interactions
Ubiquitin Thiolesterase
Protein Binding
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Nature structural & molecular biology, Nature Structural & Molecular Biology, Nature Structural and Molecular Biology, 24(3), 270
- Accession number :
- edsair.doi.dedup.....dd809f40ff4345b1e961f894b86417c0