Serial Perturbation of MinK in I Ks Implies an α-Helical Transmembrane Span Traversing the Channel Corpus

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I Ks channels contain four pore-forming KCNQ1 subunits and two accessory MinK subunits. MinK influences surface expression, voltage-dependence of gating, conduction, and pharmacology to yield the attributes characteristic of native channels in heart. The structure and location of the MinK transmembrane domain (TMD) remains a matter of scrutiny. As perturbation of gating analysis has correctly inferred the peripheral location and α-helical nature of TMDs in pore-forming subunits, the method is applied here to human MinK. Tryptophan and Asparagine substitution at 23 consecutive sites yields perturbation with α-helical periodicity (residues 44–56) followed by an alternating impact pattern (residues 56–63). Arginine substitution across the span suggests that as few as eight sites are occluded from aqueous solution (residues 50–57). We favor a TMD model that is α-helical with the external portion of the span at a lipid-protein boundary and the inner portion within the channel corpus in complex interactions.