Structural Insights into KChIP4a Modulation of Kv4.3 Inactivation.
Dynamic inactivation in Kv4 A-type K(+) current plays a critical role in regulating neuronal excitability by shaping action potential waveform and duration. Multifunctional auxiliary KChIP1-4 subunits, which share a high homology in their C-terminal core regions, exhibit distinctive modulation of inactivation and surface expression of pore-forming Kv4 subunits. However, the structural differences that underlie the functional diversity of Kv channel-interacting proteins (KChIPs) remain undetermined. Here we have described the crystal structure of KChIP4a at 3.0A resolution, which shows distinct N-terminal alpha-helices that differentiate it from other KChIPs. Biochemical experiments showed that competitive binding of the Kv4.3 N-terminal peptide to the hydrophobic groove of the core of KChIP4a causes the release of the KChIP4a N terminus that suppresses the inactivation of Kv4.3 channels. Electrophysiology experiments confirmed that the first N-terminal alpha-helix peptide (residues 1-34) of KChIP4a, either by itself or fused to N-terminal truncated Kv4.3, can confer slow inactivation. We propose that N-terminal binding of Kv4.3 to the core of KChIP4a mobilizes the KChIP4a N terminus, which serves as the slow inactivation gate.
Liang
Ping
P
Department of Neurobiology, Neuroscience Research Institute, Key Laboratory for Neuroscience of the Ministry of Education, Center for Protein Sciences, Peking University, 38 Xueyuan Road, Beijing 100083, China.
Wang
Huayi
H
Chen
Hao
H
Cui
Yuanyuan
Y
Gu
Lichuan
L
Chai
Jijie
J
Wang
Kewei
K
D000818:Animals; D018360:Crystallography, X-Ray; D051605:Kv Channel-Interacting Proteins / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D017433:Protein Structure, Secondary / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D051672:Shal Potassium Channels / Q000737:chemistry* / Q000378:metabolism; D014981:Xenopus
C455273:Kcnip4 protein, mouse; D051605:Kv Channel-Interacting Proteins; D010455:Peptides; D051672:Shal Potassium Channels