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Structure. 2017 Aug 1;25(8):1187-1194.e3. doi: 10.1016/j.str.2017.05.023. Epub 2017 Jun 29.

Crystal Structure of the CLOCK Transactivation Domain Exon19 in Complex with a Repressor.

Author information

1
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
2
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
3
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
4
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: zhang@chop.swmed.edu.

Abstract

In the canonical clock model, CLOCK:BMAL1-mediated transcriptional activation is feedback regulated by its repressors CRY and PER and, in association with other coregulators, ultimately generates oscillatory gene expression patterns. How CLOCK:BMAL1 interacts with coregulator(s) is not well understood. Here we report the crystal structures of the mouse CLOCK transactivating domain Exon19 in complex with CIPC, a potent circadian repressor that functions independently of CRY and PER. The Exon19:CIPC complex adopts a three-helical coiled-coil bundle conformation containing two Exon19 helices and one CIPC. Unique to Exon19:CIPC, three highly conserved polar residues, Asn341 of CIPC and Gln544 of the two Exon19 helices, are located at the mid-section of the coiled-coil bundle interior and form hydrogen bonds with each other. Combining results from protein database search, sequence analysis, and mutagenesis studies, we discovered for the first time that CLOCK Exon19:CIPC interaction is a conserved transcription regulatory mechanism among mammals, fish, flies, and other invertebrates.

KEYWORDS:

CIPC; CLOCK protein; Drosophila clock; circadian rhythm; coiled coil; crystal structure; repressor; transcription activation

PMID:
28669630
DOI:
10.1016/j.str.2017.05.023
[Indexed for MEDLINE]
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