Hanes Steven D
Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, 750 E Adams St., Syracuse, NY 13210 USA.
Biochim Biophys Acta. 2015 Oct;1850(10):2017-34. doi: 10.1016/j.bbagen.2014.10.028. Epub 2014 Oct 31.
Peptidyl-prolyl isomerases (PPIases) are enzymes that assist in the folding of newly-synthesized proteins and regulate the stability, localization, and activity of mature proteins. They do so by catalyzing reversible (cis-trans) rotation about the peptide bond that precedes proline, inducing conformational changes in target proteins.
This review will discuss how PPIases regulate gene transcription by controlling the activity of (1) DNA-binding transcription regulatory proteins, (2) RNA polymerase II, and (3) chromatin and histone modifying enzymes.
Members of each family of PPIase (cyclophilins, FKBPs, and parvulins) regulate gene transcription at multiple levels. In all but a few cases, the exact mechanisms remain elusive. Structure studies, development of specific inhibitors, and new methodologies for studying cis/trans isomerization in vivo represent some of the challenges in this new frontier that merges two important fields.
Prolyl isomerases have been found to play key regulatory roles in all phases of the transcription process. Moreover, PPIases control upstream signaling pathways that regulate gene-specific transcription during development, hormone response and environmental stress. Although transcription is often rate-limiting in the production of enzymes and structural proteins, post-transcriptional modifications are also critical, and PPIases play key roles here as well (see other reviews in this issue). This article is part of a Special Issue entitled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets.
肽基脯氨酰异构酶(PPIases)是一类酶,可协助新合成蛋白质的折叠,并调节成熟蛋白质的稳定性、定位和活性。它们通过催化脯氨酸前肽键的可逆(顺-反)旋转来实现这一功能,从而诱导靶蛋白的构象变化。
本综述将讨论PPIases如何通过控制(1)DNA结合转录调节蛋白、(2)RNA聚合酶II和(3)染色质及组蛋白修饰酶的活性来调节基因转录。
PPIase各家族成员(亲环蛋白、FKBP和微小蛋白)在多个水平上调节基因转录。除少数情况外,确切机制仍不清楚。结构研究、特异性抑制剂的开发以及体内顺/反异构化研究的新方法是这个融合了两个重要领域的新前沿面临的一些挑战。
脯氨酰异构酶已被发现在转录过程的所有阶段都发挥关键调节作用。此外,PPIases控制上游信号通路,这些通路在发育、激素反应和环境应激期间调节基因特异性转录。虽然转录在酶和结构蛋白的产生中通常是限速步骤,但转录后修饰也很关键,PPIases在这方面也发挥关键作用(见本期其他综述)。本文是名为“脯氨酸定向折叠酶:细胞信号催化剂和药物靶点”的特刊的一部分。