Molecular assembly of the period-cryptochrome circadian transcriptional repressor complex.
Bottom Line: Its N-terminal end tucks into CRY adjacent to a large pocket critical for CLOCK-BMAL1 binding, while its C-terminal half flanks the CRY2 C-terminal helix and sterically hinders the recognition of CRY2 by the FBXL3 ubiquitin ligase.Unexpectedly, a strictly conserved intermolecular zinc finger, whose integrity is important for clock rhythmicity, further stabilizes the complex.Our structure-guided analyses show that these interspersed CRY-interacting regions represent multiple functional modules of PERs at the CRY-binding interface.
Affiliation: Department of Pharmacology, University of Washington, Seattle, United States.Show MeSH
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Mentions: In comparison to its FBXL3-, KL001-, and FAD-complexed forms, CRY2 adopts the same global fold when bound to PER2-CBD (Figure 4—figure supplement 2). The largest structural variations take place in two local regions, the interface loop next to the FAD-binding pocket and a serine-rich loop neighboring a secondary pocket (see below). The majority of PER2-contacting residues on CRY2 (85%) are strictly conserved between mammalian CRY1 and CRY2, suggesting that the two cryptochrome proteins share a common PER2 binding mode.
Affiliation: Department of Pharmacology, University of Washington, Seattle, United States.