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.
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