INVESTIGATION OF EARLY EVENTS IN THE FOLDING OF 2 MODEL BETA SHEET PROTEINS

2 种 β 片层蛋白模型折叠早期事件的研究

• 批准号: 7601767
• 负责人: JACK JACOB
• 金额: $ 1.18万
• 依托单位: ILLINOIS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7601767
• 关键词: Antibodies; Computer Retrieval of Information on Scientific Projects Database; Data; Dimerization; Event; Fc Immunoglobulins; Funding; Grant; Immunoglobulin Domain; Institution; Investigation; Kinetics; Life; Measurement; Modeling; Optics; Play; Process; Proteins; Relative (related person); Research; Research Personnel; Resources; Role; Signal Transduction; Source; Structure; Testing; Therapeutic; Trefoil; United States National Institutes of Health; anakinra; base; beta pleated sheet; design; insight; interest; monomer; protein folding

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. We are investigating two slow folding beta-sheet proteins, the monomeric interleukin-1 receptor antagonist, IL-1ra, and the dimeric CH3 domain of immunoglobulins. Both proteins are therapeutically significant and their folding and stability is of considerable interest from both fundamental and practical standpoints. Since the CH3 domain plays a central role in the dimerization of the Fc fragment of antibodies, understanding its mechanism of folding and stabilization is valuable for designing more efficient, long-lived antibody-based therapeutics. Our understanding of protein folding often relies on kinetic modeling of optical data interpreted in terms of relative signal differences between the folded and unfolded states. The model proteins weve been investigating undergo structural transitions that cannot be unambiguously interpreted without more direct biophysical measurements. IL-1ra is a beta-trefoil protein that is structurally very similar to IL-1beta. The earliest event in the folding of IL-1beta was attributed to a collapse of the unfolded state into a partially folded state. However, only the latter event, corresponding to a slow conversion of the intermediate into the native state, was reasonably investigated. In the case of the CH3 domain again there is a lack of information on the initial events such as partial folding/collapse of the monomers possibly preceding their dimerization. It is of considerable interest to obtain more quantitative data on the early events of protein folding, such as the possibility of an initial collapse upon dilution of denaturant. IL-1ra and the CH3 domain are both small, slow folding beta-sheet proteins. However, their native structures and aggregation states are very different. By studying initial folding events of IL-1ra and the CH3 domain we may be able to see how significant and general hydrophobic collapse is. New insights into this fundamental process are invaluable since they can provide important criteria for testing existing models of protein folding.

这个子项目是众多研究子项目之一