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Elucidating Novel Topological Features in Protein Structures

阐明蛋白质结构中的新拓扑特征

基本信息

批准号：
7915388
负责人：
Todd O Yeates
金额：
$ 26.25万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2012-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Natural proteins adopt complex folded configurations. How they reach their folded configurations is a subject of intense interest. In addition, proteins must maintain stability in their native configurations, and there are open questions about how this is achieved, especially by proteins that must survive harsh conditions. Proteins that adopt particularly complex structures provide unique insights into both of these questions. This proposal focuses on the discovery and analysis of proteins whose structures reveal topological complexity, such as knotting, and linking of protein chains. Such proteins provide valuable test cases and challenging questions in the areas of protein folding and stabilization. Until recently, the possibility of naturally knotted protein chains was considered so problematic as to be nearly forbidden. But recent computational analysis of the growing structural database has revealed a few deeply knotted protein folds, and these have drawn the interest of experimentalists and theorists alike. In this proposal: (1) Using a new algorithm, we reveal a novel type of topologically complexity in the database of known protein structures: slip-knots. These are cases where a knot is created by some part of the protein chain, while the chain in its entirety appears to be unknotted. These cases, of which we have identified several, have escaped previous knot analysis. (2) We add to the set of known topologically complex proteins by determining new structures from a particular organism where we have evidence that linking and knotting are relatively common; (3) We develop a protein design strategy for converting knotted proteins into unknotted ones and vice-versa, in order to provide a test bed for studying the stabilizing effects of complex topological features in proteins. Supporting biophysical experiments are included. Biomedical relevance: The connections between human disease and protein destabilization and unfolding are becoming increasingly clear. At the present time, there are still open questions about the rules and mechanisms of protein folding. The proteins to be studied here possess unique features that make them valuable in efforts to achieve a fundamental understanding of protein structure and stability.

描述（由申请人提供）：天然蛋白质采用复杂的折叠结构。它们如何达到折叠结构是人们非常感兴趣的话题。此外，蛋白质必须保持其天然构型的稳定性，并且如何实现这一点仍存在悬而未决的问题，尤其是必须在恶劣条件下生存的蛋白质。采用特别复杂结构的蛋白质为这两个问题提供了独特的见解。该提案的重点是发现和分析其结构揭示拓扑复杂性的蛋白质，例如蛋白质链的打结和连接。此类蛋白质在蛋白质折叠和稳定领域提供了有价值的测试案例和挑战性问题。直到最近，蛋白质链自然打结的可能性还被认为存在很大问题，以至于几乎被禁止。但最近对不断增长的结构数据库的计算分析揭示了一些深度打结的蛋白质折叠，这些引起了实验学家和理论学家的兴趣。在这个提案中：（1）使用一种新算法，我们在已知蛋白质结构数据库中揭示了一种新型的拓扑复杂性：滑结。在这些情况下，蛋白质链的某些部分会打结，而整个链似乎没有打结。我们已经确定了其中的几个案例，但这些案例都逃脱了之前的结分析。 (2) 我们通过确定特定生物体的新结构来添加到已知的拓扑复杂蛋白质组中，我们有证据表明连接和打结相对常见； (3)我们开发了一种将打结蛋白转化为非打结蛋白的蛋白质设计策略，反之亦然，为研究蛋白质中复杂拓扑特征的稳定作用提供了一个试验台。包括支持生物物理实验。生物医学相关性：人类疾病与蛋白质不稳定和展开之间的联系变得越来越清晰。目前，关于蛋白质折叠的规则和机制仍然存在悬而未决的问题。这里要研究的蛋白质具有独特的特征，这使得它们对于实现对蛋白质结构和稳定性的基本了解很有价值。