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Bioorganic Basis for RNA-Protein Stability

RNA-蛋白质稳定性的生物有机基础

基本信息

批准号：
7315677
负责人：
ANNE M BARANGER
金额：
$ 25.48万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-01-01 至 2008-12-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): RNA-protein complexes are essential contributors to many important biological processes, including gene expression. An understanding of how proteins recognize RNA with high affinity and specificity will be valuable for describing and controlling these processes. The goal of this research program is to characterize the energetic contributors to RNA-protein complex formation. The proposed research will focus on the recognition of RNA by the RNA recognition motif (RRM), which is one of the most common RNA-binding domains. In the previous funding period, highly conserved aromatic amino acids that are involved in stacking interactions with RNA bases were found to be exceptional contributors to the stability of the U1A-RNA complex. In the current funding period, the molecular origins of the stabilization provided by these conserved aromatic amino acids will be investigated. Their contributions to stacking interactions in the complex, to the structures of the free protein and the complex, and to the conformational changes required upon binding will be probed by combining protein mutagenesis and synthetic modification of the RNA with structural studies, binding thermodynamic and kinetic measurements, and molecular dynamics simulations. To probe the generality of the results obtained with U1A, similar investigations with other RRM-RNA complexes will be performed. The comparison of binding in different RRM-RNA complexes will enable the identification of the energetic contributions that are held in common in RRM-RNA complexes. Finally, the RRM will be used as a template to develop small beta-hairpin peptides that bind RNA using phage display techniques. In particular, the ability of aromatic amino acids to stabilize beta-hairpin-RNA interactions will be investigated. Together, the proposed research will uncover new models for how aromatic amino acids control RNA-protein interactions. These models should be useful in the development of tools for the selective control of biological processes involving RNA-protein complexes.

描述（由申请人提供）：RNA-蛋白质复合物是许多重要生物过程（包括基因表达）的重要贡献者。了解蛋白质如何以高亲和力和特异性识别RNA对于描述和控制这些过程将是有价值的。这项研究计划的目标是表征RNA-蛋白质复合物形成的能量贡献者。该研究将集中于RNA识别基序（RRM）对RNA的识别，这是最常见的RNA结合结构域之一。在上一个资助期间，发现参与与RNA碱基堆积相互作用的高度保守的芳香族氨基酸是U1 A-RNA复合物稳定性的特殊贡献者。在目前的资助期间，将研究这些保守的芳香族氨基酸提供的稳定性的分子起源。他们的贡献堆积在复杂的相互作用，游离蛋白质和复合物的结构，并结合后所需的构象变化将探测结合蛋白质诱变和合成修饰的RNA与结构研究，结合热力学和动力学测量，和分子动力学模拟。为了探索U1 A所得结果的一般性，将对其他RRM-RNA复合物进行类似研究。不同RRM-RNA复合物中结合的比较将使得能够鉴定RRM-RNA复合物中共同持有的能量贡献。最后，RRM将用作模板，使用噬菌体展示技术开发结合RNA的小β发夹肽。特别地，将研究芳香族氨基酸稳定β-发夹-RNA相互作用的能力。总之，拟议的研究将揭示芳香族氨基酸如何控制RNA-蛋白质相互作用的新模型。这些模型应该是有用的工具，用于选择性控制涉及RNA-蛋白质复合物的生物过程的发展。