Structural and mechanistic insights into the interaction of the circadian transcription factor BMAL1 with the KIX domain of the CREB-binding protein

Sep 14, 2019The Journal of biological chemistry

How the body clock protein BMAL1 interacts with the KIX part of the CREB-binding protein

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Abstract

The BMAL1 protein's interaction with the CBP-KIX domain is critically influenced by the MLL-binding pocket.

The CLOCK:BMAL1 transcription factor complex regulates circadian transcription and chromatin modification.
Interactions between BMAL1's C-terminal domain and the KIX domain of CBP/p300 are essential for circadian oscillations.
Binding of BMAL1 to the KIX domain is weakened by the small compound 1-10, indicating the importance of the MLL-binding pocket.
Small-angle X-ray scattering models show that the N-terminal G-region of BMAL1 forms extensions from the core complex, suggesting its role in binding.
Mutations in the KIX domain's CREB-pKID/c-Myb-binding pocket moderately affect BMAL1 binding, but the BMAL1(K537Q) mutation does not impact KIX-binding affinity.

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The mammalian CLOCK:BMAL1 transcription factor complex and its coactivators CREB-binding protein (CBP)/p300 and mixed-lineage leukemia 1 (MLL1) critically regulate circadian transcription and chromatin modification. Circadian oscillations are regulated by interactions of BMAL1's C-terminal transactivation domain (TAD) with the KIX domain of CBP/p300 (activating) and with the clock protein CRY1 (repressing) as well as by the BMAL1 G-region preceding the TAD. Circadian acetylation of Lyswithin the G-region enhances repressive BMAL1-TAD-CRY1 interactions. Here, we characterized the interaction of the CBP-KIX domain with BMAL1 proteins, including the BMAL1-TAD, parts of the G-region, and LysTethering the small compound 1-10 in the MLL-binding pocket of the CBP-KIX domain weakened BMAL1 binding, and MLL1-bound KIX did not form a ternary complex with BMAL1, indicating that the MLL-binding pocket is important for KIX-BMAL1 interactions. Small-angle X-ray scattering (SAXS) models of BMAL1 and BMAL1:KIX complexes revealed that the N-terminal BMAL1 G-region including Lysforms elongated extensions emerging from the bulkier BMAL1-TAD:KIX core complex. Fitting high-resolution KIX domain structures into the SAXS-derived envelopes suggested that the G-region emerges near the MLL-binding pocket, further supporting a role of this pocket in BMAL1 binding. Additionally, mutations in the second CREB-pKID/c-Myb-binding pocket of the KIX domain moderately impacted BMAL1 binding. The BMAL1(K537Q) mutation mimicking Lysacetylation, however, did not affect the KIX-binding affinity, in contrast to its enhancing effect on CRY1 binding. Our results significantly advance the mechanistic understanding of the protein interaction networks controlling CLOCK:BMAL1- and CBP-dependent gene regulation in the mammalian circadian clock. 537 537 537 537

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Structural and mechanistic insights into the interaction of the circadian transcription factor BMAL1 with the KIX domain of the CREB-binding protein

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