Journal Article

Structural basis of gating modulation of Kv4 channel complexes

Kise, Yoshiaki, Kasuya, Go, Okamoto, Hiroyuki H., Kobayashi, Kan, Nureki, Osamu, Nakajo, Koichi, Nishizawa, Tomohiro, Yamanouchi, Daichi, Kusakizako, Tsukasa

2021

Overview

Modulation of voltage-gated potassium (Kv) channels by auxiliary subunits is central to the physiological function of channels in the brain and heart 1 , 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 potentials 1 – 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. Cryo-electron microscopy structures of the voltage-gated potassium channel Kv4.2 alone and in complex with auxiliary subunits (DPP6S and/or KChIP1) reveal the distinct mechanisms of these two different subunits in modulating channel activity.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/28 / 631/1647/1453/1970 / 631/535/1258/1259 / 9/74 / Amino acids / Animals / Back propagation / C-Terminus / Channel gating / Channels / Conformation / Cryoelectron Microscopy / Deactivation / Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - chemistry / Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - metabolism / Electron microscopy / Female / Helices / Humanities and Social Sciences / Humans / Inactivation / Intracellular / Ion Channel Gating / Kv Channel-Interacting Proteins - chemistry / Kv Channel-Interacting Proteins - metabolism / Macromolecules / Microscopy / Models, Molecular / Modulation / multidisciplinary / Multiprotein Complexes - chemistry / Multiprotein Complexes - genetics / Multiprotein Complexes - metabolism / Mutation / Nerve Tissue Proteins - chemistry / Nerve Tissue Proteins - metabolism / Oocytes - metabolism / Peptidase / Peptidases / Physiology / Potassium / Potassium channels (voltage-gated) / Potassium Channels - chemistry / Potassium Channels - metabolism / Protein Binding / Proteins / Science / Science (multidisciplinary) / Shal Potassium Channels - chemistry / Shal Potassium Channels - genetics / Shal Potassium Channels - metabolism / Xenopus laevis