7E8B

CryoEM structure of human Kv4.2-DPP6S complex

Summary for 7E8B

• Entry DOI: 10.2210/pdb7e8b/pdb
• EMDB information: 31013
• Descriptor: Dipeptidyl aminopeptidase-like protein 6, Potassium voltage-gated channel subfamily D member 2 (3 entities in total)
• Functional Keywords: membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 8
• Total formula weight: 526501.36

Authors

Kise, Y.,Nureki, O. (deposition date: 2021-03-01, release date: 2021-10-13, Last modification date: 2024-11-13)

Primary citation

Kise, Y.,Kasuya, G.,Okamoto, H.H.,Yamanouchi, D.,Kobayashi, K.,Kusakizako, T.,Nishizawa, T.,Nakajo, K.,Nureki, O.
Structural basis of gating modulation of Kv4 channel complexes.
Nature, 599:158-164, 2021

PubMed Abstract: Modulation of voltage-gated potassium (Kv) channels by auxiliary subunits is central to the physiological function of channels in the brain and heart. 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. 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.

PubMed: 34552243
DOI: 10.1038/s41586-021-03935-z

Experimental method

ELECTRON MICROSCOPY (4.2 Å)