Effective Association of Kv Channel-interacting Proteins with Kv4 Channel Is Mediated with Their Unique Core Peptide

Ren, Xiaomeng; Shand, Stuart H.; Takimoto, Koichi

doi:10.1074/jbc.m302337200

Cited by 23 publications

(20 citation statements)

References 22 publications

(17 reference statements)

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“…We crystallized a complex of the rat Kv4.3 (also called Kcnd3) N-terminal cytoplasmic domain (residues 1-143) and human KChIP1 (also called KCNIP1; residues 37-216) containing the conserved, functional KChIP core 24 . Initial crystals diffracted poorly and could not be improved.…”

Section: Results the Kchip1-kv43 N-terminal Cytoplasmic Domain Complexmentioning

confidence: 99%

Three-dimensional structure of the KChIP1–Kv4.3 T1 complex reveals a cross-shaped octamer

Pioletti

Findeisen

Hura

et al. 2006

Nat Struct Mol Biol

146

227

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Brain I A and cardiac I to currents arise from complexes containing Kv4 voltage-gated potassium channels and cytoplasmic calcium-sensor proteins (KChIPs). Here, we present X-ray crystallographic and small-angle X-ray scattering data that show that the KChIP1-Kv4.3 Nterminal cytoplasmic domain complex is a cross-shaped octamer bearing two principal interaction sites. Site 1 comprises interactions between a unique Kv4 channel N-terminal hydrophobic segment and a hydrophobic pocket formed by displacement of the KChIP H10 helix. Site 2 comprises interactions between a T1 assembly domain loop and the KChIP H2 helix. Functional and biochemical studies indicate that site 1 influences channel trafficking, whereas site 2 affects channel gating, and that calcium binding is intimately linked to KChIP folding and complex formation. Together, the data resolve how Kv4 channels and KChIPs interact and provide a framework for understanding how KChIPs modulate Kv4 function.In biological systems, electrical information is encoded and processed by changes in actionpotential timing, duration, frequency, waveform and number 1 . Modulation of voltage-gated potassium channels is central to these events and affects heart rate, sensory transduction and cognition. The ion transport 2 and voltage-dependent gating properties 3 of the potassium channel α subunits that form the ion conduction pathway are well characterized. Although α subunits form the pore, many channels function as complexes that require cytoplasmic and transmembrane auxiliary subunits 4 . To date, little is known regarding the way in which such components bind α subunits and modulate channel action. Understanding the interplay between regulatory components and pore-forming domains is crucial for unraveling how modulatory signals 4 and homeostatic mechanisms 5 allow excitable cells to sense and respond to environmental cues. Two potassium currents, I A (ref. 6 ) and I to (ref. 7 ), exert strong control over neuronal and cardiac excitability, respectively, and provide clear examples of the importance of auxiliary subunits for tuning properties of α subunits. Both currents arise from complexes of Kv4 The structure of the KChIP1-Kv4.3 T1 complex shows that the assembly forms a crossshaped octamer having the T1 tetramer at the center (Fig. 1a, chains A-D) and individual KChIPs extending radially (Fig. 1a, chains E-H). The asymmetric unit has two octameric complexes that are apposed on the cytoplasmic T1 faces (Fig. 1b). T1 shows few differences from the isolated Kv4.3 T1 structure 17 (r.m.s. deviation = 0.64 Å 2 over 408 Cα positions). In contrast, KChIP1 shows substantial differences (r.m.s. deviation = 4.03 Å 2 over 179 Cα positions) from isolated KChIP1 (ref. 17 ).The structure reveals two main interaction sites. Site 1 buries ~2,100 Å 2 total surface area between residues 3 and 21 of a conserved hydrophobic segment that is on the N-terminal side of T1 (called T1N; Fig. 2a) and a large hydrophobic pocket (28 Å long, 12 Å deep, 10 Å wide) formed by KChIP1 (Fig. 2b,c...

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Section: Results the Kchip1-kv43 N-terminal Cytoplasmic Domain Complexmentioning

confidence: 99%

Three-dimensional structure of the KChIP1–Kv4.3 T1 complex reveals a cross-shaped octamer

Pioletti

Findeisen

Hura

et al. 2006

Nat Struct Mol Biol

146

227

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“…current densities of silenced channels in CON and AP CHO cells revealed by the change in current induced by reversal of MTSET block with DTT. Currents were evoked with a voltage step to þ 5 mV from À70 mV and represent the pre-existing channels; values were determined by subtracting the pre-DTT current amplitudes from the total, post-DTT responses (n ¼ 9; *Po0.05) (myc-Kv2.1 14 ) were isolated following biotinylation and assayed by immunoblot. Consistent with our electrophysiological data, induction of apoptosis nearly doubled the biotinylated fraction of myc-Kv2.1 without any change in total channel protein ( Figure 2).…”

Section: Resultsmentioning

confidence: 99%

Apoptotic surface delivery of K+ channels

et al. 2005

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Apoptosis in cortical neurons requires efflux of cytoplasmic potassium mediated by a surge in Kv2.1 channel activity. Pharmacological blockade or molecular disruption of these channels in neurons prevents apoptotic cell death, while ectopic expression of Kv2.1 channels promotes apoptosis in non-neuronal cells. Here, we use a cysteine-containing mutant of Kv2.1 and a thiol-reactive covalent inhibitor to demonstrate that the increase in K þ current during apoptosis is due to de novo insertion of functional channels into the plasma membrane. Biotinylation experiments confirmed the delivery of additional Kv2.1 protein to the cell surface following an apoptotic stimulus. Finally, expression of botulinum neurotoxins that cleave syntaxin and synaptosome-associated protein of 25 kDa (SNAP-25) blocked upregulation of surface Kv2.1 channels in cortical neurons, suggesting that target soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins support proapoptotic delivery of K þ channels. These data indicate that trafficking of Kv2.1 channels to the plasma membrane causes the apoptotic surge in K þ current.

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“…The N-terminal KIS domain of KChIP4a, which also harbors an ER retention motif, is made responsible for these trafficking and gating effects [15,81]. In the KChIP4a splice variant the hydrophobic groove, which represents a binding domain of KChIPs for the Kv4 N-terminal helix [30,75,82], can be occupied by its own N-terminal helix in vitro (Figure 2(c)), and it was suggested that it may have to be competed out by the Kv4 N-terminus to allow Kv4/KChIP4a complex formation [83,84]. With KChIP2x and KChIP3x (= KChIP3b) Jerng and Pfaffinger [85] have identified two brain KChIP isoforms, which, like KChIP4a, contain an N-terminal KIS domain.…”

Section: Ca2+ Dependence Of Kv4/kchip Complex Formation and Membrane mentioning

confidence: 99%

Kv channel-interacting proteins as neuronal and non-neuronal calcium sensors

Bähring

2018

Channels

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Kv channel-interacting proteins (KChIPs) belong to the neuronal calcium sensor (NCS) family of Ca2+-binding EF-hand proteins. KChIPs constitute a group of specific auxiliary β-subunits for Kv4 channels, the molecular substrate of transient potassium currents in both neuronal and non-neuronal tissues. Moreover, KChIPs can interact with presenilins to control ER calcium signaling and apoptosis, and with DNA to control gene transcription. Ca2+ binding via their EF-hands, with the consequence of conformational changes, is well documented for KChIPs. Moreover, the Ca2+ dependence of the presenilin/KChIP complex may be related to Alzheimer’s disease and the Ca2+ dependence of the DNA/KChIP complex to pain sensing. However, only in few cases could the Ca2+ binding to KChIPs be directly linked to the control of excitability in nerve and muscle cells known to express Kv4/KChIP channel complexes. This review summarizes current knowledge about the Ca2+ binding properties of KChIPs and the Ca2+ dependencies of macromolecular complexes containing KChIPs, including those with presenilins, DNA and especially Kv4 channels. The respective physiological or pathophysiolgical roles of Ca2+ binding to KChIPs are discussed.

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Effective Association of Kv Channel-interacting Proteins with Kv4 Channel Is Mediated with Their Unique Core Peptide

Cited by 23 publications

References 22 publications

Three-dimensional structure of the KChIP1–Kv4.3 T1 complex reveals a cross-shaped octamer

Three-dimensional structure of the KChIP1–Kv4.3 T1 complex reveals a cross-shaped octamer

Apoptotic surface delivery of K+ channels

Kv channel-interacting proteins as neuronal and non-neuronal calcium sensors

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