文章基本信息

标题：Investigations of the underlying mechanisms of HIF-1α and CITED2 binding to TAZ1
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作者：Wen-Ting Chu ; Xiakun Chu ; Jin Wang 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2020
卷号：117
期号：11
页码：5595-5603
DOI：10.1073/pnas.1915333117
出版社：The National Academy of Sciences of the United States of America
摘要：The TAZ1 domain of CREB binding protein is crucial for transcriptional regulation and recognizes multiple targets. The interactions between TAZ1 and its specific targets are related to the cellular hypoxic negative feedback regulation. Previous experiments reported that one of the TAZ1 targets, CITED2, is an efficient competitor of another target, HIF-1α. Here, by developing the structure-based models of TAZ1 complexes, we have uncovered the underlying mechanisms of the competitions between the two intrinsic disordered proteins (IDPs) HIF-1α and CITED2 binding to TAZ1. Our results support the experimental hypothesis on the competition mechanisms and the apparent affinity. Furthermore, the simulations locate the dominant position of forming TAZ1–CITED2 complex in both thermodynamics and kinetics. For thermodynamics, TAZ1–CITED2 is the lowest basin located on the free energy surface of binding in the ternary system. For kinetics, the results suggest that CITED2 binds to TAZ1 faster than HIF-1α. In addition, the analysis of contact map and Φ values is important for guiding further experimental studies to understand the biomolecular functions of IDPs.
关键词：intrinsically disordered proteins ; competitive binding ; energy landscape ; molecular dynamics