Department of Basic Sciences, The Commonwealth Medical College, Scranton, PA 18510, USA.
Arch Biochem Biophys. 2010 Apr 15;496(2):140-5. doi: 10.1016/j.abb.2010.02.010. Epub 2010 Feb 25.
Despite their importance in gene regulation, the exact mechanisms of glucocorticoid receptor's (GR's) N-terminal activation function region, AF1, which exists in an intrinsically disordered (ID) conformation remains largely unknown. For its interaction with critical coregulatory proteins, AF1 must be malleable and capable of presenting varied interaction surfaces. We hypothesize that various confluences of effects, including intra-molecular signaling between the AF1 and the GR DNA-binding domain (DBD) cause functional structure to form in AF1. In this study, we tested the effect of the amino acid sequences surrounding AF1 on the propensity of AF1 to gain structure when connected to DBD. Removal of amino acids between AF1 and DBD results in the formation of more ordered conformation in AF1. In addition, sequences flanking the AF1 may play an inhibitory role in AF1 activity. These results suggest a mechanism as to why certain GR isoforms with truncated N-terminal domains show altered transcriptional activity.
尽管糖皮质激素受体（GR）的 N 端激活功能区 1（AF1）在基因调控中具有重要作用，但它处于一种固有无序（ID）构象，其确切机制在很大程度上仍不清楚。为了与关键的共调节蛋白相互作用，AF1 必须具有可塑性，并能够呈现不同的相互作用表面。我们假设，包括 AF1 和 GR DNA 结合域（DBD）之间的分子内信号在内的各种影响的汇合会导致 AF1 中形成功能性结构。在这项研究中，我们测试了围绕 AF1 的氨基酸序列对 AF1 与 DBD 连接时获得结构的倾向的影响。去除 AF1 和 DBD 之间的氨基酸会导致 AF1 中形成更有序的构象。此外，AF1 侧翼的序列可能在 AF1 活性中起抑制作用。这些结果表明了为什么具有截断 N 端结构域的某些 GR 同工型显示出改变的转录活性的机制。
