Redhardt, M.; Raunser, S.; Raisch, T.

Mammalian Ca2+-dependent Slo K+ channels are expressed with {beta} and {gamma} auxiliary subunits that greatly influence voltage- and Ca2+-induced gating, thereby fundamentally altering the behavior of the channel. The four {gamma} subunits reduce the need for voltage-dependent activation, allowing Slo to open in the absence of an action potential. The mechanism of this activation has, however, remained elusive. Here, we present the cryo-EM structure of Slo1 in complex with {gamma}1/LRRC26, revealing how the transmembrane helix of {gamma}1 binds and presumably stabilizes the active conformation of the voltage-sensor domain. This effect is further enhanced by a polybasic stretch on the intracellular side of the membrane which locally changes the charge gradient across the membrane. Sequence differences explain why the four {gamma} subunits possess different activation efficiencies. Simultaneous binding of {gamma} and the unrelated {beta} subunits is structurally possible, as both binding sites do not overlap and the {gamma}1 LRR domains are partially flexible. Thus, our data provide a possible explanation for Slo1 regulation by {gamma} subunits, and furthermore suggest a novel mechanism of activation of voltage-gated ion channels by auxiliary subunits and add to the growing knowledge of their complex regulation.