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Characterization of the role of COP9 signalosome in regulating ...

Characterization of the role of COP9 signalosome in regulating ...

Characterization of the role of COP9 signalosome in regulating

Characterization of the role of COP9 signalosome in regulating Cullin E3 ubiquitin ligase activity Yin Yin Choo 1 , Boon Kim Boh 1 , 2 , Jessica Jie Wei Lou 1 , Jolane Eng 1 , Yee Chin Leck 1 , Benjamin Anders 1 , Peter G. Smith 3 , Thilo Hagen 1,2 1 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 2 NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, 3 Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA ABSTRACT Cullin RING ligases (CRL) are the largest family of cellular E3 ubiquitin ligases and mediate polyubiquitination of numerous cellular substrates. CRLs are activated via the covalent modification of the cullin protein with the ubiquitin like protein Nedd8. This results in a conformational change in the cullin carboxy terminus that facilitates the ubiquitin transfer onto the substrate. CSN mediated cullin deneddylation is essential for CRL activity in vivo. However, the mechanism through which CSN promotes CRL activity in vivo is currently unclear. Here we provide evidence that cullin deneddylation is not intrinsically coupled to substrate polyubiquitination as part of the CRL activation cycle. Furthermore, inhibiting substrate receptor autoubiquitination is unlikely to account for the major mechanism through which CSN regulates CRL activity. CSN also did not affect recruitment of the substrate receptor SPOP to Cul3, suggesting it may not function to facilitate the exchange of Cul3 substrate receptors. Our results indicate that CSN binds preferentially to CRLs in the neddylation induced, active conformation. Binding of the CSN complex to active CRLs may recruit CSN associated proteins which are important for CRL regulation. The deneddylating activity of CSN would subsequently promote its own dissociation to allow progression through the CRL activation cycle. INTRODUCTION The COP9 signalosome (CSN) is an evolutionarily conserved complex consisting of 8 subunits with similarity to the lid of the 26S proteasome regulatory particle (Bosu and 1

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