title: Structure of the Cand1-Cul1-Roc1 complex reveals regulatory mechanisms for the assembly of the multisubunit cullin-dependent ubiquitin ligases.
abstract: The SCF ubiquitin ligase complex regulates diverse cellular functions by ubiquitinating numerous protein substrates. Cand1, a 120 kDa HEAT repeat protein, forms a tight complex with the Cul1-Roc1 SCF catalytic core, inhibiting the assembly of the multisubunit E3 complex. The crystal structure of the Cand1-Cul1-Roc1 complex shows that Cand1 adopts a highly sinuous superhelical structure, clamping around the elongated SCF scaffold protein Cul1. At one end, a Cand1 beta hairpin protrusion partially occupies the adaptor binding site on Cul1, inhibiting its interactions with the Skp1 adaptor and the substrate-recruiting F box protein subunits. At the other end, two Cand1 HEAT repeats pack against a conserved Cul1 surface cleft and bury a Cul1 lysine residue, whose modification by the ubiquitin-like protein, Nedd8, is able to block Cand1-Cul1 association. Together with biochemical evidence, these structural results elucidate the mechanisms by which Cand1 and Nedd8 regulate the assembly-disassembly cycles of SCF and other cullin-dependent E3 complexes.
authors.affiliation: Department of Pharmacology, Box 357280, University of Washington, Seattle, WA 98195, USA.
authors.forename: Seth J
authors.initials: SJ
authors.lastname: Goldenberg
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Cascio
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Shumway
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Garbutt
authors.forename: Jidong
authors.initials: J
authors.lastname: Liu
authors.forename: Yue
authors.initials: Y
authors.lastname: Xiong
authors.forename: Ning
authors.initials: N
authors.lastname: Zheng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000737:chemistry; D018797:Cell Cycle Proteins / Q000737:chemistry*; D003460:Crystallization; D044842:Cullin Proteins / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D044843:SKP Cullin F-Box Protein Ligases / Q000737:chemistry; D014157:Transcription Factors / Q000737:chemistry*; D025801:Ubiquitin / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000737:chemistry*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C486317:CAND1 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C100318:Cullin 1; D044842:Cullin Proteins; C430242:NUB1 protein, human; C479529:RBX1 protein, human; D014157:Transcription Factors; D025801:Ubiquitin; D043743:Ubiquitin-Protein Ligase Complexes; D044843:SKP Cullin F-Box Protein Ligases