Molecular Cloning and Characterization of CALP/KChIP4, a Novel EF-hand Protein Interacting with Presenilin 2 and Voltage-gated Potassium Channel Subunit Kv4

Morohashi, Yuichi; Hatano, Noriyuki; Ohya, Susumu; Takikawa, Rie; Watabiki, Tomonari; Takasugi, Nobumasa; Imaizumi, Yuji; Tomita, Taisuke; Iwatsubo, Takeshi

doi:10.1074/jbc.m200897200

Cited by 149 publications

(132 citation statements)

References 52 publications

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“…KChIP3 (calsenilin) was identified in a yeast two-hybrid screen using a 103 amino acid C-terminal fragment (CTF) of PS2 as a bait. With the same method, but using a 43 amino acid CTF of PS2, KChIP4 was later identified as another presenilin interaction partner, and dubbed CALP for “calsenilin-like protein” [16]. KChIP3 (calsenilin) and KChIP4 (CALP), both diffusely distributed in the cytoplasm when expressed alone, were shown to be targeted to intracellular membranes when co-expressed with PS2 [16,18].…”

Section: Kchips Interact With Presenilinsmentioning

confidence: 99%

“…With the same method, but using a 43 amino acid CTF of PS2, KChIP4 was later identified as another presenilin interaction partner, and dubbed CALP for “calsenilin-like protein” [16]. KChIP3 (calsenilin) and KChIP4 (CALP), both diffusely distributed in the cytoplasm when expressed alone, were shown to be targeted to intracellular membranes when co-expressed with PS2 [16,18]. Presenilins are part of a multi-protein γ-secretase enzyme complex, which mediates the γ-cleavage of amyloid precursor protein (APP) to produce Aβ peptides, a process which is dysregulated in Alzheimer’s disease [45].…”

Section: Kchips Interact With Presenilinsmentioning

confidence: 99%

“…These results correlated well with their pull-down experiments showing that for both KChIP1ΔEF2,3,4 and KChIP1ΔEF3,4 binding to a 143 amino acid N-terminal fragment (NTF) of Kv4.3 was impaired, and the authors concluded that Ca 2+ binding to KChIP1 EF-hands is required for Kv4.3/KChIP1 complex formation [30]. Likewise, the triple EF-hand mutant ΔEF2,3,4 of the KChIP4b1 splice variant (the initially identified CALP) was not able to modulate gating and did not coimmunoprecipitate with Kv4.2 [16], and the binding of KChIP3 to a Kv4.3 152 amino acid NTF has been shown to be Ca 2+ -dependent [72]. An and coworkers [1] showed that the KChIP1ΔEF2,3,4 mutant was unable to modulate the inactivation gating of Kv4.2, however, these authors reported (without showing the data) that KChIP1ΔEF2,3,4 coimmunoprecipitated with the Kv4.2 α-subunit, supporting the notion that Kv4.2/KChIP1 complex formation is not Ca 2+ -dependent.…”

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

confidence: 99%

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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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Section: Kchips Interact With Presenilinsmentioning

confidence: 99%

Section: Kchips Interact With Presenilinsmentioning

confidence: 99%

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

confidence: 99%

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

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2018

Channels

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“…Membrane fractions were prepared as described previously (9,28,29). The membrane pellets were resuspended in HEPES buffer to yield a protein concentration of 5-10 mg/ml and were stored at Ϫ70°C.…”

Section: Compounds and Peptides-synthesis Of Daptmentioning

confidence: 99%

Sulindac Sulfide Is a Noncompetitive γ-Secretase Inhibitor That Preferentially Reduces Aβ42 Generation

Takahashi

Hayashi

Tominari

et al. 2003

Journal of Biological Chemistry

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Nonsteroidal anti-inflammatory drugs (NSAIDs) have been known to reduce risk for Alzheimer's disease. In addition to the anti-inflammatory effects of NSAIDs to block cylooxygenase, it has been shown recently that a subset of NSAIDs selectively inhibits the secretion of highly amyloidogenic A␤42 from cultured cells, although the molecular target(s) of NSAIDs in reducing the activity of ␥-secretase for A␤42 generation (␥ 42 -secretase) still remain unknown. Here we show that sulindac sulfide (SSide) directly acts on ␥-secretase and preferentially inhibits the ␥ 42 -secretase activity derived from the 3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonate-solubilized membrane fractions of HeLa cells, in an in vitro ␥-secretase assay using recombinant amyloid ␤ precursor protein C100 as a substrate. SSide also inhibits activities for the generation of A␤40 as well as for Notch intracellular domain at higher concentrations. Notably, SSide displayed linear noncompetitive inhibition profiles for ␥ 42 -secretase in vitro. Our data suggest that SSide is a direct inhibitor of ␥-secretase that preferentially affects the ␥ 42 -secretase activity. Alzheimer's disease (AD)1 is a dementing neurodegenerative disorder of the elderly characterized pathologically by neuronal loss in the cerebral cortex accompanied by massive deposition of amyloid ␤ peptides (A␤) as senile plaques (1). A␤ is produced by sequential proteolytic cleavages of the amyloid ␤ precursor protein (␤APP) by a set of membrane-bound proteases termed ␤-and ␥-secretases. The C-terminal length of A␤ generated by ␥-secretase is heterogeneous; A␤42 is a relatively minor molecular species of the A␤ secreted from cells, but it has a much higher propensity to aggregate and form amyloid compared with other A␤ species. These findings provide strong support for the hypothesis that the deposition of A␤42 is closely related to the pathogenesis of AD, implicating ␥-secretase as an important therapeutic target.Mutations in PS1 or PS2 genes account for the majority of early onset familial AD, and these mutations cause an increase in the ratio or levels of production of A␤42 (1). It is known that PS is essential for the ␥-secretase-mediated intramembranous cleavage not only for ␤APP but for other type I transmembrane proteins (e.g. Notch, ErbB4, E-cadherin, low density lipoprotein receptor-related protein, and CD44) (2). PS proteins undergo endoproteolysis to generate N-and C-terminal fragments and interact with other proteins (i.e. nicastrin, APH-1, and PEN-2) to form a high molecular weight (HMW) protein complex (3). The functional role of PS complex in ␥-secretase activity still remains unknown. However, aspartyl protease transition state analogue inhibitors of ␥-secretase, which harbors a hydroxyl ethylene isostere or a difluoro alcohol moiety, directly label PS fragments (4 -6). In addition, a systematic analysis using a variety of PS mutants revealed that HMW complex formation of PS as well as conserved aspartyl residues within the transmembrane domain are es...

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“…Other antibodies were purchased from Chemicon (anti-PS1 loop (MAB5232)), Covance (anti-Aph-1aL (O2C2)), or Sigma (anti-Nct (N1660)). Membrane fractionation, immunoblot analysis, and immunoprecipitation of CHAPSO-solubilized lysates were performed as described previously (7,19,20). 1% digitonin-solubilized cell lysates were analyzed by Blue Native-PAGE as per the manufacturer's instructions (10).…”

Section: Methodsmentioning

confidence: 99%

Contribution of the γ-Secretase Subunits to the Formation of Catalytic Pore of Presenilin 1 Protein

Takeo

Watanabe

Tomita

et al. 2012

Journal of Biological Chemistry

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Background: ␥-Secretase, which is composed of presenilin and three subunits, is an intramembrane-cleaving protease related to Alzheimer disease. Results: Water accessibility of the catalytic pore of presenilin was decreased during assembly of active ␥-secretase. Conclusion: Binding of the subunits allosterically contributes to the formation of catalytic pore. Significance: The ␥-secretase subunits modulate the structure of presenilin.

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Molecular Cloning and Characterization of CALP/KChIP4, a Novel EF-hand Protein Interacting with Presenilin 2 and Voltage-gated Potassium Channel Subunit Kv4

Cited by 149 publications

References 52 publications

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

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

Sulindac Sulfide Is a Noncompetitive γ-Secretase Inhibitor That Preferentially Reduces Aβ42 Generation

Contribution of the γ-Secretase Subunits to the Formation of Catalytic Pore of Presenilin 1 Protein

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