title: Two helices in the third intracellular loop determine anoctamin 1 (TMEM16A) activation by calcium.
abstract: Anoctamin 1 (ANO1)/TMEM16A is a Cl(-) channel activated by intracellular Ca(2+) mediating numerous physiological functions. However, little is known of the ANO1 activation mechanism by Ca(2+). Here, we demonstrate that two helices, "reference" and "Ca(2+) sensor" helices in the third intracellular loop face each other with opposite charges. The two helices interact directly in a Ca(2+)-dependent manner. Positively and negatively charged residues in the two helices are essential for Ca(2+)-dependent activation because neutralization of these charges change the Ca(2+) sensitivity. We now predict that the Ca(2+) sensor helix attaches to the reference helix in the resting state, and as intracellular Ca(2+) rises, Ca(2+) acts on the sensor helix, which repels it from the reference helix. This Ca(2+)-dependent push-pull conformational change would be a key electromechanical movement for gating the ANO1 channel. Because chemical activation of ANO1 is viewed as an alternative means of rescuing cystic fibrosis, understanding its gating mechanism would be useful in developing novel treatments for cystic fibrosis.
authors.affiliation: Sensory Research Center, Creative Research Initiatives, College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: Jesun
authors.initials: J
authors.lastname: Lee
authors.forename: Jooyoung
authors.initials: J
authors.lastname: Jung
authors.forename: Min Ho
authors.initials: MH
authors.lastname: Tak
authors.forename: Jungwon
authors.initials: J
authors.lastname: Wee
authors.forename: Byeongjoon
authors.initials: B
authors.lastname: Lee
authors.forename: Yongwoo
authors.initials: Y
authors.lastname: Jang
authors.forename: Hyeyeon
authors.initials: H
authors.lastname: Chun
authors.forename: Dong-Jin
authors.initials: DJ
authors.lastname: Yang
authors.forename: Young Duk
authors.initials: YD
authors.lastname: Yang
authors.forename: Sang Ho
authors.initials: SH
authors.lastname: Park
authors.forename: Byung Woo
authors.initials: BW
authors.lastname: Han
authors.forename: Soonsil
authors.initials: S
authors.lastname: Hyun
authors.forename: Jaehoon
authors.initials: J
authors.lastname: Yu
authors.forename: Hawon
authors.initials: H
authors.lastname: Cho
authors.forename: H Criss
authors.initials: HC
authors.lastname: Hartzell
authors.forename: Uhtaek
authors.initials: U
authors.lastname: Oh
mesh_terms: D000075369:Anoctamin-1; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism*; D018118:Chloride Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D013499:Surface Properties; D014162:Transfection
chemical_list: C531181:ANO1 protein, mouse; D000075369:Anoctamin-1; D018118:Chloride Channels; D002118:Calcium