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Study on structural mechanism of activation by calcium of Anoctamin 1 (ANO1)/TMEM16A, calcium activated chloride channel : 칼슘의존성염소이온채널인 Anoctamin 1의 칼슘 활성화에 대한 구조기반 기전연구
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- Authors
- Advisor
- 신영기
- Major
- 약학대학 약학과
- Issue Date
- 2017-02
- Publisher
- 서울대학교 대학원
- Keywords
- The third intracellular loop (ICL3)
- Description
- 학위논문 (박사)-- 서울대학교 대학원 : 약학과, 2017. 2. 신영기.
- Abstract
- Anoctamin 1 (ANO1)/TMEM16A is a key molecule known for contributing to a variety of physiological phenomena, playing a role as calcium activated chloride channel (CaCC). Despite of the importance of the activation of ANO1 by Ca2+, it is still ambiguous to identify where Ca2+ binds to a region of ANO1 and to understand how to be activated by calcium. Here, we demonstrate that Ca2+ directly binds to the third intracellular loop (ICL3) of the ANO1 and two helices, reference and Ca2+ sensor helices in the ICL3 interact directly in a Ca2+ dependent manner as facing each other with opposite charges. Moreover neutralization or deletion of the negatively and positively charged residues in the two helices significantly changes the Ca2+ sensitivity of the ANO1. Therefore we predict a new activation mechanism by which the Ca2+ sensor helix attaches to the reference helix in the resting state, and as intracellular Ca2+ rises, Ca2+ acts on the sensor helix, which repels it from the reference helix. This Ca2+-dependent push-pull conformational change would be a key electromechanical movement for gating the ANO1 channel.
- Language
- English
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