Structural Insights into KChIP4a Modulation of Kv4.3 Inactivation

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.
Journal of Biological Chemistry (Impact Factor: 4.57). 02/2009; 284(8):4960-7. DOI: 10.1074/jbc.M807704200
Source: PubMed


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 3.0Å resolution, which shows distinct N-terminal α-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 α-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.

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Available from: Huayi Wang, Jul 03, 2014
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    • "KChIP1–4 (216 ∼ 256 amino acids) can co-immunoprecipitate and co-localize with either Kv4 from co-transfected cells or Kv4 α-subunits from tissues, and thus constitute integral components of native Kv4 channel complexes (Wang, 2008). KChIP1–4 all share a conserved carboxy-terminal core region that contains four EF-hand-like calcium binding motifs, but have a variable amino-terminal region that causes diverse modulation of Kv4 trafficking and channel function (An et al., 2000; Holmqvist et al., 2002; Scannevin et al., 2004; Cui et al., 2008; Liang et al., 2009, 2010). "
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    • "These results were confirmed using a range of techniques (biotinylation assays, on-cell westerns and electrophysiological recordings). However, a number of previous reports have found that KChIP4a, unlike other KChIP subunits, does not increase surface expression of Kv4 channels (Holmqvist et al., 2002; Jerng and Pfaffinger, 2008; Liang et al., 2008; Schwenk et al., 2008; Shibata et al., 2003). We tested a number of hypotheses to explain our results showing increased surface expression. "
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