Understanding the molecular basis of transmembrane protein association

项目摘要/摘要 我们的研究重点是了解单程膜蛋白的寡聚复合体。这个 单程蛋白是最大的一类，占所有膜蛋白的20%以上。他们是极端的 生物学意义：仅人类蛋白质组就包含2,000多种单通道膜蛋白 是众多生理功能的核心。这些单层膜的跨膜螺旋 蛋白质通常通过寡聚和构象变化发挥关键作用。了解 结构和生物物理基础这些现象对于理解生物过程中的功能至关重要， 以及许多疾病的机制。 我的实验室研究了两个互补项目的单程膜蛋白齐聚 -一个与阐明重要生物系统的结构-功能关系有关的问题，第二个目标 了解跨膜螺旋结合的一般原理。因为这些膜蛋白 用传统的结构化方法很难研究系统，我们采用了一种集成的方法论 实验方法与先进的计算建模。计算建模缓解了这一不足 实验结构，为可用实验数据提供结构解释和指导 实验设计。 我们第一个项目的目标是研究细胞膜蛋白的结构组织。 分裂体，细菌中控制细胞分裂的大型多蛋白质。尽管在以下方面取得了进展 了解它的组成部分和它们的作用，它的结构架构和它的精确 机制仍然鲜为人知。拆解这个组织对于理解 控制细菌分裂的机制。这一知识也可以支持新的 控制细菌生长的策略。 我们的第二个项目试图通过蛋白质设计来理解跨膜螺旋齐聚作用。这个 主题是最常见的跨膜二聚基序之一，GASright基序。GASright-这是 最广为人知的是血糖蛋白A二聚体的折叠-其特征是在其 界面，排列成GxxxG和类似的图案。螺旋体密切接触，促进了 形成弱Cα-H∙∙∙O=C氢键网络。我们能够通过计算来预测 GASright二聚体的结构及其相对稳定性。我们的下一个目标是通过调制测试我们的理论 通过配基结合位点的设计，这些二聚体发生二聚化和构象转换。这是 膜蛋白工程的一个几乎未被探索的领域，它与自然系统和 可能在合成生物学中有潜在的应用。

PROJECT SUMMARY/ABSTRACT Our research focuses on understanding oligomeric complexes of single-pass membrane proteins. The single-pass proteins are the largest class, comprising over 20% of all membrane proteins. They are of extreme biological importance: the human proteome alone contains over 2,000 single-pass membrane proteins which are central to a myriad of physiological functions. The transmembrane helices of these single-pass membrane proteins often play a critical role through oligomerization and conformational change. Understanding the structural and biophysical basis these phenomena is critical to understanding function in biological processes, and the mechanisms of many diseases. My laboratory studies oligomerization of single-pass membrane proteins with two complementary projects – one related to elucidating structure-function relationship in an important biological system, the second aiming to understand the general principles of transmembrane helix association. Because these membrane protein systems are difficult to study with the traditional structural methods, we apply a methodology that integrates experimental methods with advanced computational modeling. The computational modeling mitigates the lack of experimental structure, providing structural interpretation of the available experimental data and guidance for experimental designs. The goal of our first project is to investigate the structural organization of membrane proteins of the divisome, the large multi-protein that governs cell division in bacteria. Although progress has been achieved in understanding its components and their roles, the structural architecture of the divisome and its precise mechanisms are still poorly understood. Unraveling this organization is crucial for understanding the mechanisms that govern bacterial division. This knowledge could also support the development of new strategies for controlling bacterial growth. Our second project seeks to understand transmembrane helix oligomerization using protein design. The subject is one of the most common transmembrane dimerization motifs, the GASright motif. GASright – which is best known as the fold of the glycophorin A dimer – is characterized by the presence of small amino at its interface, arranged to form GxxxG and similar patterns. The helices are in close contact, promoting the formation of networks of weak Cα–H∙∙∙O=C hydrogen bonds. We are able to predict computationally the structure of GASright dimers and their relative stability. Our next goal is to test our theories by modulating dimerization and conformational switching in these dimers through the design of ligand binding sites. This is an almost unexplored area of membrane protein engineering that is extremely relevant for natural systems and could potentially have applications in synthetic biology.