Being responsible for more than 90% of cellular functions, protein molecules are workhorses in all the life forms. In order to cater for such a high demand, proteins have evolved to adopt diverse structures that allow them to perform myriad of functions. Beginning with the genetically directed amino acid sequence, the classical understanding of protein function involves adoption of hierarchically complex yet ordered structures. However, advances made over the last two decades have revealed that inasmuch as 50% of eukaryotic proteome exists as partially or fully disordered structures. Significance of such intrinsically disordered proteins (IDPs) is further realized from their ability to exhibit multifunctionality, a feature attributable to their conformational plasticity. Among the coded amino acids, cysteines are considered to be “order-promoting” due to their ability to form inter- or intramolecular disulfide bonds, which confer robust thermal stability to the protein structure in oxidizing conditions. The co-existence of order-promoting cysteines with disorder-promoting sequences seems counter-intuitive yet many proteins have evolved to contain such sequences. In this chapter, we review some of the known cysteine-containing protein domains categorized based on the number of cysteines they possess. We show that many protein domains contain disordered sequences interspersed with cysteines. We show that a positive correlation exists between the degree of cysteines and disorder within the sequences that flank them. Furthermore, based on the computational platform, IUPred2A, we show that cysteine-rich sequences display significant disorder in the reduced but not the oxidized form, increasing the potential for such sequences to function in a redox-sensitive manner. Overall, this chapter provides insights into an exquisite evolutionary design wherein disordered sequences with interspersed cysteines enable potential modulatory protein functions under stress and environmental conditions, which thus far remained largely inconspicuous.

蛋白质分子负责90％以上的细胞功能，是所有生命形式中的主力。为了满足如此高的需求，蛋白质已经进化为采用多种结构，从而使它们能够执行多种功能。从遗传指导的氨基酸序列开始，对蛋白质功能的经典理解涉及采用层次复杂但有序的结构。然而，过去二十年来的进展表明，真核蛋白质组中约有50％存在为部分或完全无序的结构。这种内在无序的蛋白质（IDP）的重要性从它们展现出多功能性的能力而进一步认识到，这种功能归因于其构象可塑性。在编码的氨基酸中，半胱氨酸由于其形成分子间或分子内二硫键的能力而被认为是“有序促进”的，在氧化条件下赋予蛋白质结构强大的热稳定性。促进顺序的半胱氨酸与促进疾病的序列并存似乎是违反直觉的，但是许多蛋白质已经进化为包含此类序列。在本章中，我们回顾了一些已知的含半胱氨酸的蛋白质结构域，这些结构域是根据它们拥有的半胱氨酸的数量进行分类的。我们表明，许多蛋白质结构域包含散布于半胱氨酸的无序序列。我们显示半胱氨酸的程度和侧翼的序列内的疾病之间存在正相关。此外，基于计算平台IUPred2A，我们表明，富含半胱氨酸的序列以还原形式而不是氧化形式显示出显着的紊乱，从而增加了此类序列以氧化还原敏感方式起作用的可能性。总的来说，本章提供了对精致的进化设计的见解，其中杂散的半胱氨酸的无序序列在压力和环境条件下使潜在的调节蛋白功能发挥了作用，到目前为止，这些功能仍然不明显。