Molecular structures of the human Slo1 K+ channel in complex with β4

Slo1 is a Ca2+- and voltage-activated K+ channel that underlies skeletal and smooth muscle contraction, audition, hormone secretion and neurotransmitter release. In mammals, Slol is regulated by auxiliary proteins that confer tissue-specific gating and pharmacological properties. This study presents cryo-EM structures of Slo1 in complex with the auxiliary protein, beta 4. Four beta 4, each containing two transmembrane helices, encircle Slot, contacting it through helical interactions inside the membrane. On the extracellular side, beta 4 forms a tetrameric crown over the pore. Structures with high and low Ca(2+ )concentrations show that identical gating conformations occur in the absence and presence of beta 4, implying that beta 4 serves to modulate the relative stabilities of 'pre-existing' conformations rather than creating new ones. The effects of beta 4 on scorpion toxin inhibition kinetics are explained by the crown, which constrains access but does not prevent binding.