SCFFBXL3 ubiquitin ligase targets cryptochromes at their cofactor pocket

Weiman Xing, Luca Busino, Thomas R. Hinds, Samuel T. Marionni, Nabiha H. Saifee, Matthew F. Bush, Michele Pagano and Ning Zheng ()
Additional contact information
Weiman Xing: Box 357280, University of Washington
Luca Busino: NYU Cancer Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, New York 10016, USA
Thomas R. Hinds: Box 357280, University of Washington
Samuel T. Marionni: Box 351700, University of Washington
Nabiha H. Saifee: Box 357280, University of Washington
Matthew F. Bush: Box 351700, University of Washington
Michele Pagano: NYU Cancer Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, New York 10016, USA
Ning Zheng: Box 357280, University of Washington

Nature, 2013, vol. 496, issue 7443, 64-68

Abstract: 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 SCFFBXL3 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.

Date: 2013
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DOI: 10.1038/nature11964

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