Intrinsically unstructured proteins: Re-assessing the protein structure-function paradigm
Intrinsically unstructured proteins: Re-assessing the protein structure-function paradigm
复制标题
DOI：
10.1006/jmbi.1999.3110
复制
发表时间：
1999-10-22
影响因子：
5.6
通讯作者：
Dyson, HJ
中科院分区：
文献类型：
--
作者：
Wright, PE;Dyson, HJ
后基因组时代的一个主要挑战将是确定编码蛋白质序列的功能。由于一般认为蛋白质的功能与其三维结构密切相关，因此预测或实验确定蛋白质结构库是一个高度优先的问题。然而，大部分基因序列似乎不是编码折叠的球状蛋白质，而是编码很长一段氨基酸，这些氨基酸可能在溶液中未折叠或采用未知构象的非球状结构。非球状蛋白序列的构象倾向和功能的表征是一个重大的挑战。这些序列在迄今为止所研究的所有生物体的基因组中所占的比例很高，这证明了它们具有重要的、迄今未知的功能，因为它们在整个进化过程中持续存在，没有其他原因。显然，折叠的三维结构对于功能是必要的这一假设需要重新审视。虽然许多蛋白质的功能与其三维结构直接相关，但许多蛋白质在生理条件下缺乏内在的球状结构，现在已经被认识到。这些蛋白质经常参与细胞中一些最重要的调节功能，并且当蛋白质与其靶分子结合时，许多情况下内在结构的缺乏得到缓解。结构的内在缺乏可以赋予蛋白质功能优势，包括结合几个不同靶点的能力。它还允许对结合过程的热力学进行精确控制：并提供了通过磷酸化或通过与细胞机器的其他组分相互作用来诱导的简单机制。在细胞周期控制以及转录和翻译调控领域，已经注意到在溶液中非结构化但在与靶结合后变得结构化的结构域的许多实例，并且非结构化结构域存在于靶向快速破坏的蛋白质中。由于这些蛋白质参与关键的细胞控制机制，因此它们的快速周转，在未结合状态下的非结构化性质的帮助下，提供了一定水平的控制，允许细胞对变化的环境条件做出快速和准确的反应。(C)北京：科学出版社.
A major challenge in the post-genome era will be determination of the functions of the encoded protein sequences. Since it is generally assumed that the function of a protein is closely linked to its three-dimensional structure, prediction or experimental determination of the library of protein structures is a matter of :high priority. However, a large proportion of gene sequences appear to;code not for folded, globular proteins, but for long stretches of amino acids that are likely to be either unfolded in solution or adopt non-globular structures of unknown conformation. Characterization of the conformational propensities and function of the non-globular protein sequences represents a major challenge. The high proportion of these sequences in the genomes of all organisms studied to date argues for important, as yet unknown functions,since there could be no other reason for their persistence throughout evolution. Clearly the assumption that a folded three-dimensional: structure is necessary-for function needs to be re-examined. Although the functions of many proteins are directly related to their three-dimensional structures, numerous proteins that lack intrinsic globular structure under; physiological conditions have now been recognized. Such proteins are frequently involved in some of the most important regulatory functions in the cell, and the lack of intrinsic structure in:many cases is relieved when:the protein binds to its target molecule. The intrinsic lack of structure can confer functional advantages on a protein, including the ability to bind to several different targets. It also allows precise control over the thermodynamics of the binding process: and provides a simple mechanism for inducibility by phosphorylation or through interaction with other components of the cellular machinery. Numerous examples of domains that are unstructured in solution but which become structured upon binding to the target have been noted in the areas of cell cycle control and both transcriptional and translational regulation, and unstructured domains are present in proteins that are targeted for rapid destruction.:Since such proteins participate in critical cellular control mechanisms, it appears Likely that their rapid turnover,: aided by their unstructured nature in the unbound state, provides a-level of control that allows rapid and accurate responses of the cell to changing environmental conditions. (C) 1999 Academic Press.