2GWF

Structure of a USP8-NRDP1 complex

Summary for 2GWF

• Entry DOI: 10.2210/pdb2gwf/pdb
• Related: 1WHB 2A9U 2FZP 2GFO
• Descriptor: Ubiquitin carboxyl-terminal hydrolase 8, RING finger protein 41 (3 entities in total)
• Functional Keywords: protein-protein complex, e3 ligase, protein ubiquitination, hydrolase, protease, ubl conjugation pathway, structural genomics, structural genomics consortium, sgc, hydrolase-ligase complex, hydrolase/ligase
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm: P40818
• Total number of polymer chains: 6
• Total formula weight: 98292.61

Authors

Walker, J.R.,Avvakumov, G.V.,Xue, S.,Newman, E.M.,Butler-Cole, C.,Finerty Jr., P.J.,Weigelt, J.,Sundstrom, M.,Arrowsmith, C.H.,Edwards, A.M.,Bochkarev, A.,Dhe-Paganon, S.,Structural Genomics Consortium (SGC) (deposition date: 2006-05-04, release date: 2006-06-06, Last modification date: 2024-02-14)

Primary citation

Avvakumov, G.V.,Walker, J.R.,Xue, S.,Finerty Jr., P.J.,Mackenzie, F.,Newman, E.M.,Dhe-Paganon, S.
Amino-terminal Dimerization, NRDP1-Rhodanese Interaction, and Inhibited Catalytic Domain Conformation of the Ubiquitin-specific Protease 8 (USP8).
J.Biol.Chem., 281:38061-38070, 2006

PubMed 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.

PubMed: 17035239
DOI: 10.1074/jbc.M606704200

Experimental method

X-RAY DIFFRACTION (2.3 Å)