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1.A.114.  The Proton-activated Chloride Channel (PACC) Family 

Severe local acidosis causes tissue damage and pain, and is one of the hallmarks of many diseases including ischemia, cancer, and inflammation. Yang et al. 2019 performed an unbiased RNA interference screen and identified PAC (TMEM206) as being essential for the widely observed proton-activated Cl- (PAC) currents (I Cl,H). Overexpression of human PAC in PAC knockout cells generated I Cl,H with the same characteristics as the endogenous ones. Zebrafish PAC encodes a PAC channel with distinct properties. Knockout of mouse Pac abolished I Cl,H in neurons and attenuated brain damage after ischemic stroke. The wide expression of PAC suggests a broad role for this conserved Cl- channel family in physiological and pathological processes associated with acidic pH (Yang et al. 2019). 

Ullrich et al. 2019 used a genome-wide siRNA screen to molecularly identify the widely expressed acid-sensitive outwardly-rectifying anion channel PAORAC/ASOR. ASOR is formed by TMEM206 proteins which display two TMSs and are expressed at the plasma membrane. Ion permeation-changing mutations along the length of TMS2 and at the end of TMS1 suggest that these segments line ASOR's pore. TMEM206 has orthologs in probably all vertebrates, but possibly not in other orgamism. Currents from evolutionarily distant orthologs share activation by protons, a feature essential for ASOR's role in acid-induced cell death (Ullrich et al. 2019). 

PAC is active across a wide range of mammalian cells and is involved in acid-induced cell death and tissue injury. Ruan et al. 2020 presented two cryo-EM structures of human PAC in a high-pH resting closed state and a low-pH proton-bound non-conducting state. PAC is a trimer in which each subunit consists of a transmembrane domain (TMD), which is formed of two helices (TMS1 and TMS2), and an extracellular domain (ECD). Upon a decrease of pH from 8 to 4, a conformational change in the ECD-TMD interface and the TMD is observed. The rearrangement of the ECD-TMD interface is characterized by the movement of the histidine 98 residue, which is, after acidification, decoupled from the resting position and inserted into an acidic pocket that is about 5 Å away. Within the TMD, TMS1 undergoes a rotational movement, switching its interaction partner from its cognate TMS2 to the adjacent TMS2. The anion selectivity of PAC is determined by the positively charged lysine 319 residue in TMS2, and replacing lysine 319 with a glutamate residue converts PAC to a cation-selective channel (Ruan et al. 2020).

References associated with 1.A.114 family:

Deng, Z., Y. Zhao, J. Feng, J. Zhang, H. Zhao, M.J. Rau, J.A.J. Fitzpatrick, H. Hu, and P. Yuan. (2021). Cryo-EM structure of a proton-activated chloride channel TMEM206. Sci Adv 7:. 33627432
Maeda, S.I., R. Aoba, Y. Nishino, and T. Omata. (2019). A novel bacterial nitrate transporter composed of small transmembrane proteins. Plant Cell Physiol. [Epub: Ahead of Print] 31198965
Ruan, Z., J. Osei-Owusu, J. Du, Z. Qiu, and W. Lü. (2020). Structures and pH-sensing mechanism of the proton-activated chloride channel. Nature. [Epub: Ahead of Print] 33149300
Ullrich, F., S. Blin, K. Lazarow, T. Daubitz, J.P. von Kries, and T.J. Jentsch. (2019). Identification of TMEM206 proteins as pore of PAORAC/ASOR acid-sensitive chloride channels. Elife 8:. 31318332
Yang, J., J. Chen, M. Del Carmen Vitery, J. Osei-Owusu, J. Chu, H. Yu, S. Sun, and Z. Qiu. (2019). PAC, an evolutionarily conserved membrane protein, is a proton-activated chloride channel. Science 364: 395-399. 31023925