FOLDING AND ASSEMBLY OF DIMERIC BETA-BARREL PROTEINS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。理解无规卷曲的多肽链如何折叠成具有独特三维结构的功能酶是生物学中最重要的悬而未决的问题之一。成功解决这一根本问题将导致生物技术和蛋白质错误折叠相关疾病的治疗取得重大进展。肌萎缩侧索硬化症(Lou Gehrig病)是一种神经退行性疾病，在这种疾病中，一种蛋白质(铜，锌超氧化物歧化酶，SOD)的错误折叠被假设在功能获得毒性中发挥作用。因此，了解这种二聚体β-桶蛋白的能量格局对于揭示可能与毒性相关的部分折叠状态的动力学和结构性质是重要的。为了测试其折叠机制并探索其部分折叠状态的结构特性，我们对apo-SOD进行了时间分辨的SAXS研究。这项研究的目的是确定坍塌、二级结构形成和二聚化发生的顺序。这项研究是美国国立卫生研究院资助的一个综合性项目的一部分，该项目研究了两种二聚体β-桶蛋白apo-SOD和HIV-1蛋白酶的折叠机制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. An understanding of how a random-coil polypeptide chain folds into a functional enzyme with a unique three-dimensional structure is one of the most significant unresolved questions in biology. Success in solving this fundamental problem will lead to significant advances in biotechnology and treatment of diseases related to protein misfolding. Amyotrophic lateral sclerosis (Lou Gehrig's disease) is an example of a neurodegenerative disease in which misfolding of a protein (Cu, Zn superoxide dismutase, SOD) has been hypothesized to play a role in the gain-of-function toxicity. Understanding the energy landscape of this dimeric beta-barrel protein is therefore important for revealing the dynamics and structural properties of partially-folded states that may be relevant to toxicity. To test the folding mechanism and probe the structural properties of the partially folded states of SOD we conducted a time-resolved SAXS study of apo-SOD. The goal of the study was to determine the sequence in which collapse, secondary structure formation and dimerization occur. This study was part of a comprehensive NIH-funded project examining the folding mechanism of two dimeric beta-barrel proteins, apo-SOD and HIV-1 protease.