Kewley Robyn J, Whitelaw Murray L, Chapman-Smith Anne
School of Molecular and Biomedical Science (Biochemistry), University of Adelaide, Adelaide, SA 5005, Australia.
Int J Biochem Cell Biol. 2004 Feb;36(2):189-204. doi: 10.1016/s1357-2725(03)00211-5.
Basic helix-loop-helix (bHLH)/PAS proteins are critical regulators of gene expression networks underlying many essential physiological and developmental processes. These include transcriptional responses to environmental pollutants and low oxygen tension, mediated by the aryl hydrocarbon (Dioxin) receptor and hypoxia inducible factors (HIF), respectively, and controlling aspects of neural development, mediated by the single minded (SIM) proteins. bHLH proteins must dimerise to form functional DNA binding complexes and bHLH/PAS proteins are distinguished from other members of the broader bHLH superfamily by the dimerisation specificity conferred by their PAS homology domains. bHLH/PAS proteins tend to be ubiquitous, latent signal-regulated transcription factors that often recognise variant forms of the classic E-box enhancer sequence bound by other bHLH proteins. Two closely related forms of each of the hypoxia inducible factors alpha and single minded proteins and the general partner protein, aryl hydrocarbon receptor nuclear translocator (ARNT), are present in many cell types. Despite high sequence conservation within their DNA binding and dimerisation domains, and having very similar DNA recognition specificities, the homologues are functionally non-redundant and biologically essential. While the mechanisms controlling partner choice and target gene activation that determine this functional specificity are poorly understood, interactions mediated by the PAS domains are essential. Information on structures and protein/protein interactions for members of the steroid hormone/nuclear receptor superfamily has contributed to our understanding of the way these receptors function and assisted the development of highly specific agonists and antagonists. Similarly, it is anticipated that developing a detailed mechanistic and structural understanding of bHLH/PAS proteins will ultimately facilitate drug design.
碱性螺旋-环-螺旋（bHLH）/PAS蛋白是许多重要生理和发育过程中基因表达网络的关键调节因子。这些过程包括分别由芳烃（二噁英）受体和缺氧诱导因子（HIF）介导的对环境污染物和低氧张力的转录反应，以及由单 minded（SIM）蛋白介导的神经发育控制。bHLH蛋白必须二聚化以形成功能性DNA结合复合物，而bHLH/PAS蛋白通过其PAS同源结构域赋予的二聚化特异性与更广泛的bHLH超家族的其他成员区分开来。bHLH/PAS蛋白往往是普遍存在的、潜伏的信号调节转录因子，它们通常识别其他bHLH蛋白结合的经典E-box增强子序列的变体形式。缺氧诱导因子α和单 minded蛋白以及通用伴侣蛋白芳烃受体核转运蛋白（ARNT）的两种密切相关形式存在于许多细胞类型中。尽管它们的DNA结合和二聚化结构域内序列保守性高，且具有非常相似的DNA识别特异性，但这些同源物在功能上并非冗余，而是生物学上必不可少的。虽然决定这种功能特异性的控制伴侣选择和靶基因激活的机制尚不清楚，但由PAS结构域介导的相互作用是必不可少的。关于类固醇激素/核受体超家族成员的结构和蛋白质/蛋白质相互作用的信息有助于我们理解这些受体的功能方式，并辅助开发高度特异性的激动剂和拮抗剂。同样，预计对bHLH/PAS蛋白进行详细的机制和结构研究最终将促进药物设计。
