2gwf
Structure of a USP8-NRDP1 complex
OverviewOverview
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.
About this StructureAbout this Structure
2GWF is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Amino-terminal dimerization, NRDP1-rhodanese interaction, and inhibited catalytic domain conformation of the ubiquitin-specific protease 8 (USP8)., Avvakumov GV, Walker JR, Xue S, Finerty PJ Jr, Mackenzie F, Newman EM, Dhe-Paganon S, J Biol Chem. 2006 Dec 8;281(49):38061-70. Epub 2006 Oct 11. PMID:17035239 Page seeded by OCA on Sun May 4 05:37:10 2008
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- Homo sapiens
- Protein complex
- Ubiquitin thiolesterase
- Arrowsmith, C H.
- Avvakumov, G V.
- Bochkarev, A.
- Butler-Cole, C.
- Dhe-Paganon, S.
- Edwards, A M.
- Jr., P J.Finerty.
- Newman, E M.
- SGC, Structural Genomics Consortium.
- Sundstrom, M.
- Walker, J R.
- Weigelt, J.
- Xue, S.
- E3 ligase
- Hydrolase
- Protease
- Protein ubiquitination
- Protein-protein complex
- Sgc
- Structural genomic
- Structural genomics consortium
- Ubl conjugation pathway