The intrinsically disordered proteins and protein regions (IDPs/IDPRs) do not have unique structures, but are known to be functionally important and their conformational flexibility and structural plasticity have engendered a paradigmatic shift in the classical sequence-structure-function maxim. Fundamental understanding in this field has significantly evolved since the discovery of this class of proteins about 25 years ago. Though the IDPRs of transmembrane proteins (TMP-IDPRs) comply with the broad definition of typical IDPs and IDPRs found in water-soluble globular proteins, much less is explored and known about them. In this review, we assimilate the key emerging biophysical principles from the limited studies on TMP-IDPRs and provide several context-specific biological examples to highlight the ubiquitous nature of TMP-IDPRs and their functional importance in cellular functions. Besides providing a spectrum of insights from sequence to structural disorder and functions, we also review the challenges and methodological advances in studying the structure-function relationship of TMP-IDPRs. We also lay stress upon the importance of an integrative framework, where ensemble-averaged (and mostly low-resolution) data from multiple experiments can be faithfully integrated with modelling techniques such as advanced sampling, coarse-graining, and free energy minimization methods for a high-fidelity characterization of TMP-IDPRs. We close the review by providing futuristic perspective with suggestions on how we could use the ideas and methods from the exciting field of protein engineering in conjunction with integrative modelling framework to advance the IDPR field and harness the sequence-disorder-function paradigm towards functional design of proteins.

中文翻译：

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跨膜蛋白内在无序区域的结构和功能多样性。

内在无序的蛋白质和蛋白质区域（IDP / IDPR）没有独特的结构，但是功能上很重要，它们的构象柔韧性和结构可塑性已引起经典序列结构-功能最大化。自从大约25年前发现这类蛋白质以来，该领域的基本理解已经有了显着发展。尽管跨膜蛋白（TMP-IDPRs）的IDPR符合在水溶性球状蛋白中发现的典型IDP和IDPR的广泛定义，但对它们的探索和了解却很少。在这篇评论中 我们从对TMP-IDPR的有限研究中吸收了关键的新兴生物物理原理，并提供了一些针对特定环境的生物学实例，以突出TMP-IDPR的普遍性质及其在细胞功能中的功能重要性。除了提供从序列到结构紊乱和功能的广泛见解之外，我们还回顾了研究TMP-IDPR的结构-功能关系方面的挑战和方法学进展。我们还强调了集成框架的重要性，在该框架中，可以将来自多个实验的整体平均（且大多数为低分辨率）数据与建模技术如高级采样，粗粒度和自由能最小化方法如实地集成在一起。 TMP-IDPR的高保真特性。