Two helices in the third intracellular loop determine anoctamin 1 TMEM16A activation by calciumReportar como inadecuado

Two helices in the third intracellular loop determine anoctamin 1 TMEM16A activation by calcium - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Journal Title:

Pflügers Archiv European Journal of Physiology


Volume 467, Number 8


SpringerOpen | 2015-08-01, Pages 1677-1687

Type of Work:

Article | Final Publisher PDF

Abstract: Anoctamin 1 ANO1-TMEM16A is a Cl−<-sup> channel activated by intracellular Ca2+<-sup> mediating numerous physiological functions. However, little is known of the ANO1 activation mechanism by Ca2+<-sup>. Here, we demonstrate that two helices -reference- and -Ca2+<-sup> sensor- helices in the third intracellular loop face each other with opposite charges. The two helices interact directly in a Ca2+<-sup>-dependent manner. Positively and negatively charged residues in the two helices are essential for Ca2+<-sup>-dependent activation because neutralization of these charges change the Ca2+<-sup> sensitivity. We now predict that the Ca2+<-sup> sensor helix attaches to the reference helix in the resting state, and as intracellular Ca2+<-sup> rises, Ca2+<-sup> acts on the sensor helix, which repels it from the reference helix. This Ca2+<-sup>-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.

Subjects: Health Sciences, Pharmacy - Chemistry, Pharmaceutical - Research Funding: This research was supported by a grant from the National Research Foundation of Korea no. 20110018358, a grant from BK21+ program of Ministry of Education of Korea, and NIH grants GM60448 and EY114852 HCH

Keywords: Science and Technology - Life Sciences and Biomedicine - Physiology - Anoctamin 1 - Anoctamin 2 - Calcium - Activation - Helix - Structure - CA2+-ACTIVATED CL-CHANNELS - CHLORIDE CHANNELS - ENDOTHELIAL-CELLS - GNATHODIAPHYSEAL-DYSPLASIA - PROTEIN - CURRENTS - AMPLIFICATION - EXPRESSION - CLONING - NEURONS -

Autor: Jesun Lee, Jooyoung Jung, Min Ho Tak, Jungwon Wee, Byeongjoon Lee, Yongwoo Jang, Hyeyeon Chun, Dong-Jin Yang, Young Duk Yang, San



Documentos relacionados