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2.
Cell ; 124(1): 105-17, 2006 Jan 13.
Article in English | MEDLINE | ID: mdl-16413485

ABSTRACT

The DDB1-Cul4A ubiquitin ligase complex promotes protein ubiquitination in diverse cellular functions and is reprogrammed by the V proteins of paramyxoviruses to degrade STATs and block interferon signaling. Here we report the crystal structures of DDB1 alone and in complex with the simian virus 5 V protein. The DDB1 structure reveals an intertwined three-propeller cluster, which contains two tightly coupled beta propellers with a large pocket in between and a third beta propeller flexibly attached on the side. The rigid double-propeller fold of DDB1 is targeted by the viral V protein, which inserts an entire helix into the double-propeller pocket, whereas the third propeller domain docks DDB1 to the N terminus of the Cul4A scaffold. Together, these results not only provide structural insights into how the virus hijacks the DDB1-Cul4A ubiquitin ligase but also establish a structural framework for understanding the multiple functions of DDB1 in the uniquely assembled cullin-RING E3 machinery.


Subject(s)
Cullin Proteins/chemistry , DNA-Binding Proteins/chemistry , Genes, Viral , Protein Structure, Tertiary , Ubiquitin-Protein Ligases/chemistry , Viral Structural Proteins/chemistry , Crystallization , Crystallography, X-Ray , Cullin Proteins/genetics , Cullin Proteins/physiology , DNA-Binding Proteins/physiology , Humans , Models, Molecular , Mutagenesis, Site-Directed , Protein Conformation , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/physiology , Viral Structural Proteins/genetics , Viral Structural Proteins/physiology
3.
Cell ; 119(4): 517-28, 2004 Nov 12.
Article in English | MEDLINE | ID: mdl-15537541

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.


Subject(s)
Cell Cycle Proteins/chemistry , Cullin Proteins/chemistry , Transcription Factors/chemistry , Ubiquitin-Protein Ligase Complexes/chemistry , Adaptor Proteins, Signal Transducing , Carrier Proteins/chemistry , Crystallization , Humans , Models, Molecular , Molecular Conformation , Protein Binding , SKP Cullin F-Box Protein Ligases/chemistry , Ubiquitin/metabolism
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