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  • 02월 23일 15시 이후 : 초록수정 불가능, 일정확인 및 검색만 가능

Metastablility of native form of α1-antitrypsin and its role in functional regulation

2009년 2월 23일 14시 27분 14초
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생명화학 - Protein-Folding & Disease
저자 및
이철주, 유명희1, 백제현1, 강운범
한국과학기술연구원, 생체과학연구본부, Korea
1프로테오믹스이용기술개발사업단, Korea
The native form of α1-antitrypsin (A1AT) is a metastable conformation with a protruding reactive site loop (RSL). The native form converts into a more stable form when the protein forms a complex with a target protease and the RSL is inserted into the central beta sheet of A1AT. Mutational analyses and structural examination of A1AT reveal unusual interactions, such as side-chain overpacking, buried polar groups, and cavities as the structural basis of the native metastability. Removal of such unusual interactions by site-directed mutagenesis occasionally increases the stability of the native form. Stabilization of native structure in turn brings about activity loss possibly due to deterioration in conformational switch during complex formation with a target protease. Analysis of a circular purmutant of A1AT suggests preferential folding of the protein to the metastable native conformation is driven by rapid folding of the hydrophobic core with concomitant formation of third beta-sheet that holds the RSL. Functional studies on disulfide-engineered A1AT mutants and hydrogen-deuterium exchange experiment on the A1AT-protease complex reveal more detailed nature about functional unfolding of A1AT during complex formation. A substantial portion of the A1AT molecule, not restricted to the central beta sheet or the RSL, seems to unfold transiently during complex formation. All the results hitherto acquired strongly suggest that the native metastability of A1AT is indeed a structural design that regulates protein functions.