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Amino-terminal dimerization, NRDP1-rhodanese interaction, and inhibited catalytic domain conformation of the ubiquitin-specific protease 8 (USP8).
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2006 Dec 08; Vol. 281 (49), pp. 38061-70. Date of Electronic Publication: 2006 Oct 11. - Publication Year :
- 2006
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Abstract
- Ubiquitin-specific protease 8 (USP8) hydrolyzes mono and polyubiquitylated targets such as epidermal growth factor receptors and is involved in clathrin-mediated internalization. In 1182 residues, USP8 contains multiple domains, including coiled-coil, rhodanese, and catalytic domains. We report the first high-resolution crystal structures of these domains and discuss their implications for USP8 function. The amino-terminal domain is a homodimer with a novel fold. It is composed of two five-helix bundles, where the first helices are swapped, and carboxyl-terminal helices are extended in an antiparallel fashion. The structure of the rhodanese domain, determined in complex with the E3 ligase NRDP1, reveals the canonical rhodanese fold but with a distorted primordial active site. The USP8 recognition domain of NRDP1 has a novel protein fold that interacts with a conserved peptide loop of the rhodanese domain. A consensus sequence of this loop is found in other NRDP1 targets, suggesting a common mode of interaction. The structure of the carboxyl-terminal catalytic domain of USP8 exhibits the conserved tripartite architecture but shows unique traits. Notably, the active site, including the ubiquitin binding pocket, is in a closed conformation, incompatible with substrate binding. The presence of a zinc ribbon subdomain near the ubiquitin binding site further suggests a polyubiquitin-specific binding site and a mechanism for substrate induced conformational changes.
- Subjects :
- Catalytic Domain
Crystallography, X-Ray
Dimerization
Endopeptidases genetics
Endosomal Sorting Complexes Required for Transport
Humans
In Vitro Techniques
Kinetics
Models, Molecular
Multiprotein Complexes
Protein Structure, Quaternary
Protein Structure, Tertiary
Recombinant Proteins chemistry
Recombinant Proteins genetics
Recombinant Proteins metabolism
Static Electricity
Thiosulfate Sulfurtransferase genetics
Ubiquitin Thiolesterase
Ubiquitin-Protein Ligases genetics
Endopeptidases chemistry
Endopeptidases metabolism
Thiosulfate Sulfurtransferase chemistry
Thiosulfate Sulfurtransferase metabolism
Ubiquitin-Protein Ligases chemistry
Ubiquitin-Protein Ligases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 281
- Issue :
- 49
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 17035239
- Full Text :
- https://doi.org/10.1074/jbc.M606704200