Revisiting allostery in CREB-binding protein (CBP) using residue-based interaction energy
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Revisiting allostery in CREB-binding protein (CBP) using residue-based interaction energy Metin Yazar1,2 · Pemra Ozbek1 Received: 18 December 2019 / Accepted: 13 May 2020 © Springer Nature Switzerland AG 2020
Abstract CREB-binding protein (CBP) is a multi-subunit scaffold protein complex in transcription regulation process, binding and interacting with ligands such as mixed-lineage leukemia (MLL) and c-Myb allosterically. Here in this study, we have revisited the concept of allostery in CBP via residue-based interaction energy calculation based on molecular dynamics (MD) simulations. To this end, we conducted MD simulations of KIX:MLL:c-Myb ternary complex, its binary components and kinase-inducible domain (KID) interacting domain (KIX) backbone. Interaction energy profiles and cross correlation analysis were performed and the results indicated that KIX:MLL and KIX:c-Myb:MLL complexes demonstrate significant similarities according to both analysis methods. Two regions in the KIX backbone were apparent from the interaction energy and cross correlation maps that hold a key to allostery phenomena observed in CBP. While one of these regions are related to the ligand binding residues, the other comprises of L 12–G2 loop and α3 helix regions that have been found to have a significant role in allosteric signal propagation. All in all, residue-based interaction energy calculation method is demonstrated to be a valuable calculation technique for the detection of allosteric signal propagation and ligand interaction regions. Keywords CREB binding protein (CBP) · Allostery · Residue-based interaction energy · Molecular dynamics simulations · Motional correlation analysis
Introduction CREB-binding protein (CBP) is a transcriptional scaffold protein responsible for the regulation of RNA polymerase mediated transcription [1]. CBP and its paralog P300, which are indicated to play an important role in cell growth, transformation and development, are types of transcriptional machinery [2]. CBP is generally a bridge between DNA and general transcription factors and is responsible for relaxation of chromatin structure through intrinsic histone acetyltransferase (HAT) activity [3]. Also, acetylation Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10822-020-00316-y) contains supplementary material, which is available to authorized users. * Pemra Ozbek [email protected] 1
Department of Bioengineering, Marmara University, Göztepe, Istanbul, Turkey
Department of Genetics and Bioengineering, Istanbul Okan University, Tuzla, Istanbul, Turkey
2
of some transcription factors can be regulated via CBP, so transcriptional regulation and chromatin-remodelling can be performed through the modulation of the expression and activation of the coactivators of CBP (Fig. 1a) [4, 5]. There are seven folded interacting domains in CBP that create the formation of multi-protein assemble machinery in binding with transcription factors, signaling molecules and hormone receptors (Fig.
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