title: CRAC channel gating and its modulation by STIM1 and 2-aminoethoxydiphenyl borate.
abstract: Ca2+release-activated Ca2+(CRAC) channels play an essential role in the immune system. The pore-forming subunit, Orai1, is an important pharmacological target. Here, we summarize the recent discoveries on the structure-function relationship of Orai1, as well as its interaction with the native channel opener STIM1 and chemical modulator 2-aminoethoxydiphenyl borate (2-APB). We first introduce the critical structural elements of Orai1, which include a Ca2+accumulating region, ion selectivity filter, hydrophobic centre, basic region, extended transmembrane Orai1 N-terminal (ETON) region, transmembrane (TM) regions 2 and 3, P245 bend,263SHK265hinge linker and L273-L276 hydrophobic patch. We then hypothesize the possible mechanisms by which STIM1 triggers the conformational transitions of TM regions and exquisitely shapes the ion conduction pathway during generation of the CRAC current (Icrac) with high Ca2+selectivity. Finally, we propose mechanisms by which 2-APB modulates Icrac. On the STIM1-activated Orai1 channel, a low dose of 2-APB acts directly, dilating its extremely narrow pore diameter from 3.8 to 4.6 Å, increasing its unitary channel conductance, and potentiating the Icrac. Further elucidation of the structure of the opened CRAC channel and a better understanding of structure-function relationship will benefit the future development of novel immune modulators.
authors.affiliation: National Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.|University of Chinese Academy of Science, Beijing, 100049, China.
authors.forename: Sher
authors.initials: S
authors.lastname: Ali
authors.affiliation: National Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Xu
authors.affiliation: National Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
authors.forename: Xiaolan
authors.identifier: 0000-0002-7120-177X
authors.initials: X
authors.lastname: Xu
mesh_terms: D001896:Boron Compounds / Q000494:pharmacology*; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D009363:Neoplasm Proteins / Q000502:physiology*; D000071740:ORAI1 Protein / Q000737:chemistry* / Q000502:physiology*; D000071737:Stromal Interaction Molecule 1 / Q000502:physiology*
chemical_list: D001896:Boron Compounds; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; C109986:2-aminoethoxydiphenyl borate
keywords: 2-APB; CRAC channel; channel gating; ion channel modulation