Modulation of Pore Opening of Eukaryotic Sodium Channels by π-Helices in S6

Choudhury, KoushikKTH,Biofysik,Science for Life Laboratory, SciLifeLab (författare)

QC 20230706
Voltage-gated sodium channels are heterotetrameric sodiumselectiveion channels that play a central role in electrical signaling in excitablecells. With recent advances in structural biology, structures of eukaryoticsodium channels have been captured in several distinct conformationscorresponding to different functional states. The secondary structureof the pore lining S6 helices of subunits DI, DII, and DIV has beencaptured with both short & pi;-helix stretches and in fully & alpha;-helicalconformations. The relevance of these secondary structure elementsfor pore gating is not yet understood. Here, we propose that a & pi;-helixin at least DI-S6, DIII-S6, and DIV-S6 results in a fully conductivestate. On the other hand, the absence of & pi;-helix in either DI-S6or DIV-S6 yields a subconductance state, and its absence from bothDI-S6 and DIV-S6 yields a nonconducting state. This work highlightsthe impact of the presence of a & pi;-helix in the different S6helices of an expanded pore on pore conductance, thus opening newdoors toward reconstructing the entire conformational landscape alongthe functional cycle of Nav Channels and paving the way to the design of state-dependent modulators.

Delemotte, LucieKTH,Biofysik,Science for Life Laboratory, SciLifeLab(Swepub:kth)u15w0he7 (författare)
KTHBiofysik (creator_code:org_t)

Ingår i:The Journal of Physical Chemistry Letters: American Chemical Society (ACS)14:25, s. 5876-58811948-7185

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