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Cell Chem Biol ; 31(5): 1000-1010.e6, 2024 May 16.
Article in English | MEDLINE | ID: mdl-38113885

ABSTRACT

Acid-sensing ion channels (ASICs) are trimeric ion channels that open a cation-conducting pore in response to proton binding. Excessive ASIC activation during prolonged acidosis in conditions such as inflammation and ischemia is linked to pain and stroke. A conserved lysine in the extracellular domain (Lys211 in mASIC1a) is suggested to play a key role in ASIC function. However, the precise contributions are difficult to dissect with conventional mutagenesis, as replacement of Lys211 with naturally occurring amino acids invariably changes multiple physico-chemical parameters. Here, we study the contribution of Lys211 to mASIC1a function using tandem protein trans-splicing (tPTS) to incorporate non-canonical lysine analogs. We conduct optimization efforts to improve splicing and functionally interrogate semisynthetic mASIC1a. In combination with molecular modeling, we show that Lys211 charge and side-chain length are crucial to activation and desensitization, thus emphasizing that tPTS can enable atomic-scale interrogations of membrane proteins in live cells.


Subject(s)
Acid Sensing Ion Channels , Lysine , Acid Sensing Ion Channels/metabolism , Acid Sensing Ion Channels/chemistry , Acid Sensing Ion Channels/genetics , Lysine/chemistry , Lysine/metabolism , Humans , Animals , Models, Molecular , Protein Splicing
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