Wright P E, Dyson H J
Department of Molecular Biology and Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
J Mol Biol. 1999 Oct 22;293(2):321-31. doi: 10.1006/jmbi.1999.3110.
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.
后基因组时代的一项重大挑战将是确定编码蛋白质序列的功能。由于人们普遍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当务之急。然而，很大一部分基因序列似乎并非编码折叠的球状蛋白质，而是编码长串的氨基酸，这些氨基酸在溶液中可能是未折叠的，或者采用未知构象的非球状结构。表征非球状蛋白质序列的构象倾向和功能是一项重大挑战。在迄今为止研究的所有生物体的基因组中，这些序列的高比例表明它们具有重要的、尚未知晓的功能，因为在整个进化过程中它们持续存在不可能有其他原因。显然，认为功能需要折叠的三维结构这一假设需要重新审视。尽管许多蛋白质的功能与其三维结构直接相关，但现在已经认识到许多在生理条件下缺乏内在球状结构的蛋白质。这类蛋白质经常参与细胞中一些最重要的调节功能，而且在许多情况下，当蛋白质与其靶分子结合时，内在结构的缺乏会得到缓解。内在的结构缺乏可以赋予蛋白质功能优势，包括与几种不同靶标结合的能力。它还允许对结合过程的热力学进行精确控制，并提供一种通过磷酸化或与细胞机制的其他成分相互作用实现诱导性的简单机制。在细胞周期控制以及转录和翻译调控领域，已经注意到许多在溶液中无结构但在与靶标结合时会形成结构的结构域实例，并且在靶向快速降解的蛋白质中也存在无结构结构域。由于这类蛋白质参与关键的细胞控制机制，它们在未结合状态下的无结构性质有助于其快速周转，这似乎提供了一种控制水平，使细胞能够对不断变化的环境条件做出快速而准确的反应。
