TM INTERACTIONS IN MEMBRANE PROTEIN FOLDING AND FUNCTION

描述（由申请人提供）：跨膜螺旋之间的相互作用是膜蛋白结构的主要特征。理解指导这种相互作用的原理将阐明膜蛋白的折叠、稳定性和低聚物的形成。由于膜蛋白由超过20%的基因编码，并且是超过一半的药物的靶标，因此这种理解将具有启发性和实用性。我们将致力于理解产生跨膜螺旋（TM）相互作用的基序和相互作用，这些相互作用稳定了生物膜中的蛋白质结构，并开始将我们的理解与生物功能联系起来。我们已经为TM相互作用的研究开发了一个多样化的工具包，包括：(a)胶束、双层和膜的遗传和生化分析，(b)计算方法，以及(c)使用光谱学和核磁共振的结构研究。我们的方法将分为几个主要部分：研究HIV gp41 TM和MHC li中的TM三聚体；寻找螺旋二聚化与信号传导之间联系的努力；相互作用母题研究；TM-TM计算方法的改进；以及可以在螺旋关联中识别的原理和基序的测试。

DESCRIPTION (provided by applicant): Interactions between transmembrane helices are a major feature of the architecture of membrane proteins. Understanding the principles that guide such interactions will illuminate membrane protein folding, stability, and oligomer formation. Since membrane proteins are coded by more than 20% of all genes and are the targets of more than half of all drugs, such an understanding will be both enlightening and useful. We will work towards understanding the motifs and interactions that give rise to transmembrane helix (TM) interactions that stabilize protein structures in biological membranes, and to begin to connect our understanding to biological functions. We have developed a diverse toolkit for the study of TM interactions, including: (a) genetic and biochemical assays in micelles, bilayers and membranes, (b) computational approaches, and (c) structural studies using optical spectroscopy and NMR. Our approach will have several major divisions: a study of TM trimers in HIV gp41 TMs and MHC li; an effort to find the link between helix dimerization and signaling; a study of interaction motifs; an improvement of TM-TM computational methods; and tests of the principles and motifs that can be identified in helix associations.