Adaptor protein self-assembly drives the control of a cullin-RING ubiquitin ligase.
The E3 ligases recruit substrate proteins for targeted ubiquitylation. Recent insights into the mechanisms of ubiquitylation demonstrate that E3 ligases can possess active regulatory properties beyond those of a simple assembly scaffold. Here, we describe the dimeric structure of the E3 ligase adaptor protein SPOP (speckle-type POZ protein) in complex with the N-terminal domain of Cul3 at 2.4 Å resolution. We find that SPOP forms large oligomers that can form heteromeric species with the closely related paralog SPOPL. In combination, SPOP and SPOPL (SPOP-like) form a molecular rheostat that can fine-tune E3 ubiquitin ligase activity by affecting the oligomeric state of the E3 complex. We propose that adaptor protein self-assembly provides a graded level of regulation of the SPOP/Cul3 E3 ligase toward its multiple protein substrates.
Department of Biochemistry, University of Toronto, 1 Kings College Circle, Toronto, Ontario M5S 1A8, Canada.
Wesley J
WJ
Errington
M Qasim
MQ
Khan
Stephanie A
SA
Bueler
John L
JL
Rubinstein
Avijit
A
Chakrabartty
Gilbert G
GG
Privé
D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D044842:Cullin Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010957:Plasmids; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D040681:Structural Homology, Protein; D025801:Ubiquitin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
C503645:CUL3 protein, human; D044842:Cullin Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D011994:Recombinant Proteins; D012097:Repressor Proteins; C509761:SPOP protein, human; D025801:Ubiquitin