title: F-box-directed CRL complex assembly and regulation by the CSN and CAND1.
abstract: The COP9 signalosome (CSN) is thought to maintain the stability of cullin-RING ubiquitin ligases (CRL) by limiting the autocatalytic destruction of substrate adapters such as F box proteins (FBPs). CAND1, a protein associated with unneddylated CUL1, was proposed to assist in this role in an as yet unclear fashion. We found that only a subset of Schizosaccharomyces pombe FBPs, which feature a critical F box proline that promotes their interaction with CUL1, required CSN for stability. Unlike the CRL3 adaptor Btb3p, none of the CSN-sensitive FBPs were affected by deletion of ubp12. Contrary to current models, CAND1 does not control adaptor stability but maintains the cellular balance of CRL1 complexes by preventing rare FBPs from being outcompeted for binding to CUL1 by more ample adapters. These findings were integrated into a refined model of CRL control in which substrate availability toggles CRLs between independent CSN and CAND1 cycles.
authors.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Schmidt
authors.forename: Philip R
authors.initials: PR
authors.lastname: McQuary
authors.forename: Susan
authors.initials: S
authors.lastname: Wee
authors.forename: Kay
authors.initials: K
authors.lastname: Hofmann
authors.forename: Dieter A
authors.initials: DA
authors.lastname: Wolf
mesh_terms: D000595:Amino Acid Sequence; D016203:CDC2 Protein Kinase / Q000378:metabolism; D000075686:COP9 Signalosome Complex; D017124:Conserved Sequence; D044842:Cullin Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism; D044783:F-Box Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D045726:Metalloproteases / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism*; D011392:Proline; D011485:Protein Binding; D055550:Protein Stability; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D012568:Schizosaccharomyces / Q000201:enzymology* / Q000235:genetics; D029702:Schizosaccharomyces pombe Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014452:Ubiquitins / Q000378:metabolism
chemical_list: D044842:Cullin Proteins; D044783:F-Box Proteins; D046912:Multiprotein Complexes; C499610:Ned8 protein, S pombe; C449205:Pof10 protein, S pombe; C514993:Pof3 protein, S pombe; D029702:Schizosaccharomyces pombe Proteins; D014452:Ubiquitins; D011392:Proline; D044843:SKP Cullin F-Box Protein Ligases; C504781:SKP1 protein, S pombe; D016203:CDC2 Protein Kinase; C469447:cdc2 protein, S pombe; D010450:Endopeptidases; D045726:Metalloproteases; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex; C506284:Csn5 protein, S pombe; C474614:Ubp12 protein, S pombe