Structural basis of gating modulation of Kv4 channel complexes

Area of Science:

• Neuroscience
• Structural Biology
• Molecular Biology

Background:

• Voltage-gated potassium (Kv) channels are crucial for neuronal and cardiac function.
• Kv4 channels form complexes with KChIPs and DPPs to generate A-type currents, essential for action potential propagation.
• The precise mechanisms of modulation by these auxiliary subunits are not fully understood.

Purpose of the Study:

• To elucidate the structural basis of Kv4 channel modulation by KChIP1 and DPP6S.
• To understand how these interactions contribute to the formation of A-type currents.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to determine the structures of Kv4.2 alone and in complex with KChIP1 and DPP6S.
• Analysis of the obtained structures to identify subunit interfaces and conformational changes.

Main Results:

• The cryo-EM structure of the Kv4.2-KChIP1 complex shows KChIP1 binding to both N and C termini of Kv4.2, stabilizing the S6 gating helix.
• The structure of Kv4.2-DPP6S reveals DPP6S interaction with the S1-S2 helices of the voltage-sensing domain, stabilizing this region.
• KChIP1 and DPP6S do not directly interact within the ternary complex.

Conclusions:

• KChIP1 modulates Kv4 channel gating by preventing N-type inactivation and stabilizing the S6 conformation.
• DPP6S modulates Kv4 channel gating by stabilizing the voltage-sensing domain, potentially accelerating S4 helix movement.
• These distinct modulatory mechanisms act additively to generate native A-type currents.