4I6J

A ubiquitin ligase-substrate complex

Summary for 4I6J

• Entry DOI: 10.2210/pdb4i6j/pdb
• Related: 4I6E 4I6G
• Descriptor: Cryptochrome-2, F-box/LRR-repeat protein 3, S-phase kinase-associated protein 1, ... (4 entities in total)
• Functional Keywords: circadian clock, ubiquitination, lrr, f-box, photolyase fold, periods, nucleus, transcription
• Biological source: Mus musculus (mouse); More
• Cellular location: Cytoplasm: Q9R194; Nucleus: Q9UKT7
• Total number of polymer chains: 3
• Total formula weight: 129292.57

Authors

Xing, W.,Busino, L.,Hinds, T.R.,Marionni, S.T.,Saifee, N.H.,Bush, M.F.,Pagano, M.,Zheng, N. (deposition date: 2012-11-29, release date: 2013-03-13, Last modification date: 2024-10-09)

Primary citation

Xing, W.,Busino, L.,Hinds, T.R.,Marionni, S.T.,Saifee, N.H.,Bush, M.F.,Pagano, M.,Zheng, N.
SCFFBXL3 ubiquitin ligase targets cryptochromes at their cofactor pocket.
Nature, 496:64-68, 2013

PubMed Abstract: The cryptochrome (CRY) flavoproteins act as blue-light receptors in plants and insects, but perform light-independent functions at the core of the mammalian circadian clock. To drive clock oscillations, mammalian CRYs associate with the Period proteins (PERs) and together inhibit the transcription of their own genes. The SCF(FBXL3) ubiquitin ligase complex controls this negative feedback loop by promoting CRY ubiquitination and degradation. However, the molecular mechanisms of their interactions and the functional role of flavin adenine dinucleotide (FAD) binding in CRYs remain poorly understood. Here we report crystal structures of mammalian CRY2 in its apo, FAD-bound and FBXL3-SKP1-complexed forms. Distinct from other cryptochromes of known structures, mammalian CRY2 binds FAD dynamically with an open cofactor pocket. Notably, the F-box protein FBXL3 captures CRY2 by simultaneously occupying its FAD-binding pocket with a conserved carboxy-terminal tail and burying its PER-binding interface. This novel F-box-protein-substrate bipartite interaction is susceptible to disruption by both FAD and PERs, suggesting a new avenue for pharmacological targeting of the complex and a multifaceted regulatory mechanism of CRY ubiquitination.

PubMed: 23503662
DOI: 10.1038/nature11964

Experimental method

X-RAY DIFFRACTION (2.7 Å)