Abstract
Modulation of voltage-gated potassium (Kv) channels by auxiliary subunits is central to the physiological function of channels in the brain and heart1,2. Native Kv4 tetrameric channels form macromolecular ternary complexes with two auxiliary β-subunits—intracellular Kv channel-interacting proteins (KChIPs) and transmembrane dipeptidyl peptidase-related proteins (DPPs)—to evoke rapidly activating and inactivating A-type currents, which prevent the backpropagation of action potentials1–5. However, the modulatory mechanisms of Kv4 channel complexes remain largely unknown. Here we report cryo-electron microscopy structures of the Kv4.2–DPP6S–KChIP1 dodecamer complex, the Kv4.2–KChIP1 and Kv4.2–DPP6S octamer complexes, and Kv4.2 alone. The structure of the Kv4.2–KChIP1 complex reveals that the intracellular N terminus of Kv4.2 interacts with its C terminus that extends from the S6 gating helix of the neighbouring Kv4.2 subunit. KChIP1 captures both the N and the C terminus of Kv4.2. In consequence, KChIP1 would prevent N-type inactivation and stabilize the S6 conformation to modulate gating of the S6 helices within the tetramer. By contrast, unlike the reported auxiliary subunits of voltage-gated channel complexes, DPP6S interacts with the S1 and S2 helices of the Kv4.2 voltage-sensing domain, which suggests that DPP6S stabilizes the conformation of the S1–S2 helices. DPP6S may therefore accelerate the voltage-dependent movement of the S4 helices. KChIP1 and DPP6S do not directly interact with each other in the Kv4.2–KChIP1–DPP6S ternary complex. Thus, our data suggest that two distinct modes of modulation contribute in an additive manner to evoke A-type currents from the native Kv4 macromolecular complex.
Highlights
Among 12 subfamilies of Kv channels, Kv4 (Kv4.1–Kv4.3) channels mediate the transient outward A-type current, which is characterized by fast activation at subthreshold membrane potentials, fast inactivation and fast recovery from the inactivated state[3,4]
Kv4.2–KChIP1 and the Kv4.2–DPP6S–KChIP1 complexes. c, The intracellular S6 helix of Kv4.2 alone bends at the interface on the T1–S1 linker and is subsequently disordered
It keeps a close distance to the T1–S1 linker without bending in the Kv4.2–KChIP1 and the Kv4.2–DPP6S–KChIP1 complexes
Summary
Among 12 subfamilies of Kv channels, Kv4 (Kv4.1–Kv4.3) channels mediate the transient outward A-type current, which is characterized by fast activation at subthreshold membrane potentials, fast inactivation and fast recovery from the inactivated state[3,4]. The N terminus of Kv4 reportedly serves as the inactivation ball when Kv4 is expressed alone[20], Kv4s close the gate immediately with unknown mechanisms and end up in a closed inactivated state irrespective of the magnitude of depolarization (that is, CSI), from which they recover with fast kinetics[12,21,22] (Extended Data Fig. 1). The N terminus of Kv4s20 (Extended Data Fig. 1b) It remains unknown how KChIP modulates other gating properties of CSI and recovery. To gain insight into the mechanisms of gating modulation of Kv4s by KChIPs and DPPs, we determined the structures of full-length Kv4.2 alone, the Kv4.2–KChIP1 and Kv4.2–DPP6S binary complexes, and the Kv4.2–DPP6S–KChIP1 macromolecular ternary complex by single-particle cryo-electron microscopy (cryo-EM) (Fig. 1)
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