Modeling of Protein Complexes and Missense Mutations

描述(申请人提供)：人类蛋白质中的氨基酸突变通常与特定疾病的遗传易感性有关。然而，大多数观察到的错义多态，即那些涉及单个核苷酸变化导致氨基酸变化的错义多态，还没有根据它们对蛋白质结构和功能的影响来表征。我们假设，许多最有害的错义突变以两种方式之一影响蛋白质功能：1)通过改变蛋白质与其他分子的相互作用，包括其他蛋白质、DMA和小配体；或2)通过改变蛋白质的稳定性。这两种机制主要取决于突变的位置及其物理性质：蛋白质相互作用的变化通常是由结合位点的突变引起的；稳定性的变化通常是由埋藏的疏水残基的突变引起的。这项建议的目的是开发一个计算系统，通过蛋白质复合体的同源建模来预测错义突变的功能影响。将获得两个二聚体酶系统中1000个随机突变的新功能数据，以训练和测试该模型。这个计算系统的主要应用将是与发育相关的基因 癌症。癌症通常与许多基因变化有关，其中一些是遗传的，另一些是躯体的。这些包括DNA损伤修复的丧失，细胞周期检查点的崩溃，以及对细胞凋亡的抵抗。这些过程中的每一个都需要许多蛋白质相互作用，通常是在大型蛋白质复合体中。这些相互作用可能会被错义突变或降低蛋白质稳定性的突变所破坏，错义突变会改变分子之间的个体相互作用。

DESCRIPTION (provided by applicant): Amino acid mutations in human proteins are often associated with inherited predispositions to specific diseases. Yet most observed missense polymorphisms, those involving a single nucleotide change leading to a changed amino acid, have not been characterized in terms of their effects on protein structure and function. We hypothesize that many of the most deleterious missense mutations affect protein function in one of two ways: 1) by altering interaction of proteins with other molecules, including other proteins, DMA, and small ligands; or 2) by altering stability of the protein. Both of these mechanisms depend primarily on the location of the mutation and its physical properties: changes in protein interactions are usually caused by mutations in or very near to a binding site; changes in stability are usually caused by mutations of buried hydrophobic residues. The aim of this proposal is to develop a computational system for predicting the functional effects of missense mutations through homology modeling of protein complexes. New functional data on 1000 random mutations in two dimeric enzyme systems will be obtained to train and test the model. The primary application of this computational system will be to genes associated with the development of cancer. Cancer is usually linked to a number of genetic changes, some inherited and others somatic. These include loss of DNA-damage repair, breakdown of cell-cycle checkpoints, and resistance to apoptosis. Each of these processes requires many protein interactions, often in large protein complexes. These interactions may be compromised by missense mutations that alter individual interactions between molecules or mutations that lower protein stability.