3DQV

Structural Insights into NEDD8 Activation of Cullin-RING Ligases: Conformational Control of Conjugation

Summary for 3DQV

• Entry DOI: 10.2210/pdb3dqv/pdb
• Descriptor: NEDD8, Cullin-5, Rbx1, ... (4 entities in total)
• Functional Keywords: ubiquitin, nedd8, scf, cullin-ring ligase, cullin, nucleus, ubl conjugation pathway, host-virus interaction, receptor, ubl conjugation, acetylation, cytoplasm, dna damage, dna repair, metal-binding, zinc, zinc-finger, signaling protein, ligase
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: Q15843; Cytoplasm: P62877
• Total number of polymer chains: 6
• Total formula weight: 134119.07

Authors

Duda, D.M.,Borg, L.A.,Scott, D.C.,Hunt, H.W.,Hammel, M.,Schulman, B.A. (deposition date: 2008-07-09, release date: 2008-09-30, Last modification date: 2024-10-30)

Primary citation

Duda, D.M.,Borg, L.A.,Scott, D.C.,Hunt, H.W.,Hammel, M.,Schulman, B.A.
Structural insights into NEDD8 activation of cullin-RING ligases: conformational control of conjugation.
Cell(Cambridge,Mass.), 134:995-1006, 2008

PubMed Abstract: Cullin-RING ligases (CRLs) comprise the largest ubiquitin E3 subclass, in which a central cullin subunit links a substrate-binding adaptor with an E2-binding RING. Covalent attachment of the ubiquitin-like protein NEDD8 to a conserved C-terminal domain (ctd) lysine stimulates CRL ubiquitination activity and prevents binding of the inhibitor CAND1. Here we report striking conformational rearrangements in the crystal structure of NEDD8~Cul5(ctd)-Rbx1 and SAXS analysis of NEDD8~Cul1(ctd)-Rbx1 relative to their unmodified counterparts. In NEDD8ylated CRL structures, the cullin WHB and Rbx1 RING subdomains are dramatically reoriented, eliminating a CAND1-binding site and imparting multiple potential catalytic geometries to an associated E2. Biochemical analyses indicate that the structural malleability is important for both CRL NEDD8ylation and subsequent ubiquitination activities. Thus, our results point to a conformational control of CRL activity, with ligation of NEDD8 shifting equilibria to disfavor inactive CAND1-bound closed architectures, and favor dynamic, open forms that promote polyubiquitination.

PubMed: 18805092
DOI: 10.1016/j.cell.2008.07.022

Experimental method

X-RAY DIFFRACTION (3 Å)