Structural Insights into the CRTC2–CREB Complex Assembly on CRE. Issue 13 (22nd June 2018)

• Record Type: Journal Article
• Authors: Song, Yihui; Zhai, Liting; Valencia Swain, Jonathan; Chen, Yaqiong; Wang, Pengfei; Chen, Li; Liu, Yi; Xiang, Song
• Is Part Of: Journal of molecular biology. Volume 430:Issue 13(2018)
• Page Start: 1926
• Page End: 1939
• Publication Date: 2018-06-22
• Subjects: transcription factor -- CRE -- CREB -- CRTC -- X-ray crystallography; CRE cAMP response element -- CREB CRE binding protein -- CBP CREB-binding protein -- CRTCs CREB-regulated transcriptional coactivators -- CBD CREB binding domain -- bZip basic leucine zipper -- SeMet selenomethionine -- FP fluorescence polarization -- GST glutathione S-transferase; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2018.04.038
• Languages: English
• ISSNs: 0022-2836

Abstract

Abstract: The cAMP response element (CRE) binding protein (CREB) is central in the transcription regulation by cAMP, and the CREB-regulated transcriptional coactivators (CRTCs) play critical roles in CREB-mediated transcription activation. Upon stimulation, CRTCs translocate into the nucleus and complex with CREB on CRE promoters to activate target gene transcription. Their physiological importance is underscored by their function in energy balance, long-term memory, longevity and other processes. The CREB binding domain on CRTCs has been mapped, which interacts with the CREB basic leucine zipper domain that also mediates interaction with CRE-containing DNA. We report here crystal structures of a complex containing the CRTC2 CREB binding domain, the CREB basic leucine zipper domain and a CRE-containing DNA. The structures revealed that CRTC and CREB form a 2:2 complex on CRE-containing DNA, and CRTC interacts with both CREB and DNA through highly conserved residues. Structure-guided functional studies revealed that both interactions are crucial for the complex assembly and CREB stabilization on DNA. Interestingly, we found that the CRTC–DNA interaction confers selectivity toward the intrinsic DNA shape, which may play a role in selective transcription activation of the CRE genes. Graphical abstract: Unlabelled Image Highlights: Crystal structure of the CRTC2–CREB–CRE complex Structural insights into the CRTC–CREB interaction The CRTC–DNA interaction is essential for the CRTC–CREB–CRE complex assembly. The CRTC–DNA interaction stabilizes CREB on DNA. The CRTC–DNA interaction confers selectivity toward the intrinsic DNA shape.