title: CAND1 enhances deneddylation of CUL1 by COP9 signalosome.
abstract: Cullin-RING ligases (CRLs) regulate diverse cellular functions such as cell cycle progression and cytokine signaling by ubiquitinating key regulatory proteins. The activity of CRLs is controlled by Nedd8 modification of the cullin subunits. Recent reports have suggested that CAND1, which specifically binds to unmodified CUL1 but not to neddylated one, is required for the in vivo function of SCFs, the CUL1-containing CRLs. We show here that CAND1 and COP9 signalosome (CSN), the major deneddylase of cullins, bind to unneddylated CUL1 in a mutually exclusive way. The suppression of CAND1 expression by small inhibitory RNA enhanced the interaction between CUL1 and CSN, suggesting that CAND1 inhibited the binding of CSN to CUL1. We found that the binding of CSN to CUL1 required the four helix bundle in CUL1 C-terminal domain, which was wrapped around by CAND1 in the CAND1-CUL1-Rbx1 complex. CAND1 greatly facilitated CSN-mediated deneddylation of CUL1 in vitro, which was dependent on its binding to CUL1. Our data suggest that enhancement of CSN-mediated deneddylation by CAND1 may contribute to its function as a positive regulator of SCFs in vivo.
authors.affiliation: Department of Biochemistry and Protein Network Research Center, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Kyoeng-Woo
authors.initials: KW
authors.lastname: Min
authors.forename: Mun-Jin
authors.initials: MJ
authors.lastname: Kwon
authors.forename: Hyoung-Seo
authors.initials: HS
authors.lastname: Park
authors.forename: Yoon
authors.initials: Y
authors.lastname: Park
authors.forename: Sungjoo Kim
authors.initials: SK
authors.lastname: Yoon
authors.forename: Jong-Bok
authors.initials: JB
authors.lastname: Yoon
mesh_terms: D000075686:COP9 Signalosome Complex; D018797:Cell Cycle Proteins / Q000378:metabolism*; D044842:Cullin Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D046912:Multiprotein Complexes / Q000378:metabolism*; D000075687:NEDD8 Protein; D010447:Peptide Hydrolases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D014157:Transcription Factors / Q000502:physiology*; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: C486317:CAND1 protein, human; D018797:Cell Cycle Proteins; C100318:Cullin 1; D044842:Cullin Proteins; D046912:Multiprotein Complexes; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D014157:Transcription Factors; D014452:Ubiquitins; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex