Cis-trans isomerization at a proline opens the pore of a neurotransmitter-gated ion channel.
5-hydroxytryptamine type 3 (5-HT3) receptors are members of the Cys-loop receptor superfamily. Neurotransmitter binding in these proteins triggers the opening (gating) of an ion channel by means of an as-yet-uncharacterized conformational change. Here we show that a specific proline (Pro 8*), located at the apex of the loop between the second and third transmembrane helices (M2- M3), can link binding to gating through a cis-trans isomerization of the protein backbone. Using unnatural amino acid mutagenesis, a series of proline analogues with varying preference for the cis conformer was incorporated at the 8* position. Proline analogues that strongly favour the trans conformer produced non-functional channels. Among the functional mutants there was a strong correlation between the intrinsic cis-trans energy gap of the proline analogue and the activation of the channel, suggesting that cis-trans isomerization of this single proline provides the switch that interconverts the open and closed states of the channel. Consistent with this proposal, nuclear magnetic resonance studies on an M2- M3 loop peptide reveal two distinct, structured forms. Our results thus confirm the structure of the M2- M3 loop and the critical role of Pro 8* in the 5-HT3 receptor. In addition, they suggest that a molecular rearrangement at Pro 8* is the structural mechanism that opens the receptor pore.[1]References
- Cis-trans isomerization at a proline opens the pore of a neurotransmitter-gated ion channel. Lummis, S.C., Beene, D.L., Lee, L.W., Lester, H.A., Broadhurst, R.W., Dougherty, D.A. Nature (2005) [Pubmed]
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