Calcium-regulated DNA Binding and Oligomerization of the Neuronal Calcium-sensing Protein, Calsenilin/DREAM/KChIP3

Osawa, Masatoshi; Tong, Kit I.; Lilliehöök, Christina; Wasco, Wilma; Buxbaum, Joseph D.; Cheng, He‐Hsiung; Penninger, Josef; Ikura, Mitsuhiko; Ames, James B.

doi:10.1074/jbc.m105842200

Cited by 122 publications

(153 citation statements)

References 29 publications

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“…Even an EF3,EF4 fragment (amino acid 161 – 256) of KChIP3 showed a reduced spectral resolution in the absence of Ca 2+ , corroborating the central role of EF3 and EF4 in Ca 2+ binding and associated conformational changes [40]. KChIPs may also form oligomers in a divalent cation-dependent manner, with Ca 2+ binding to EF3 and EF4 favoring dimer formation [33,39,41]. KChIP3 has even been reported to oligomerize with calcineurin and calmodulin [42].…”

Section: Ca2+ Binding Properties and Associated Conformational Changementioning

confidence: 89%

“…An increase in Ca 2+ leads to conformational changes and a dissociation of KChIP3 (DREAM) from the DRE site in an EF-hand-dependent manner, which allows transcription of the prodynorphin gene [19]. Thus, in nociceptive spinal cord neurons the prodynorphin gene is switched on during massive action potential firing with elevated cytoplasmic Ca 2+ levels, to modulate pain perception via κ-opioid receptors [19,41,65]. In an analogous manner the Na + /Ca 2+ exchanger (NCX) 3 expression in cerebellar neurons is under the control of the transcriptional repressor KChIP3 (DREAM), which may occupy a doublet of DRE sites in the NCX3 gene when Ca 2+ is low [55].…”

Section: Kchips Control Gene Transcriptionmentioning

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: Ca2+ Binding Properties and Associated Conformational Changementioning

confidence: 89%

Section: Kchips Control Gene Transcriptionmentioning

confidence: 99%

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

Bähring

2018

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“…Analogous Ca 21 triggered bathochromic shifts were reported previously, although the emission spectra presented here are approximately 5 nm blue shifted compared with the published results. 24 The protein was purified and studied in the presence of LDAO since the previous study had shown that the addition of LDAO reduces protein aggregation and stabilizes apoDREAM and Ca 21 DREAM in its tetrameric and dimeric form, respectively. 24 We have observed that the presence of LDAO strongly impacts the emission spectra of Ca 21 free and Ca 21 bound DREAM.…”

Section: Steady-state Emission Spectramentioning

confidence: 99%

“…24 The protein was purified and studied in the presence of LDAO since the previous study had shown that the addition of LDAO reduces protein aggregation and stabilizes apoDREAM and Ca 21 DREAM in its tetrameric and dimeric form, respectively. 24 We have observed that the presence of LDAO strongly impacts the emission spectra of Ca 21 free and Ca 21 bound DREAM. For example, DREAM samples dialyzed against 20 mM Tris buffer, 1 mM DTT, and 10 mM LDAO at pH 7.4 for 48 h provided emission spectra with a k max of 340 nm and 335 nm for apo-and Ca 21 DREAM, respectively, which are comparable to those reported by Osawa et al 24 On the other hand, emission spectra of DREAM samples prepared in the absence of LDAO are blue shifted with an emission maximum at $330 nm for Ca 21 21 association to DREAM leads to a conformational transition upon which the Trp residue moves towards the hydrophobic core of the protein.…”

Section: Steady-state Emission Spectramentioning

confidence: 99%

Ca²⁺ and Mg²⁺ modulate conformational dynamics and stability of downstream regulatory element antagonist modulator

et al. 2015

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Downstream Regulatory Element Antagonist Modulator (DREAM) belongs to the family of neuronal calcium sensors (NCS) that transduce the intracellular changes in Ca 21 concentration into a variety of responses including gene expression, regulation of Kv channel activity, and calcium homeostasis. Despite the significant sequence and structural similarities with other NCS members, DREAM shows several features unique among NCS such as formation of a tetramer in the apo-state, and interactions with various intracellular biomacromolecules including DNA, presenilin, Kv channels, and calmodulin. Here we use spectroscopic techniques in combination with molecular dynamics simulation to study conformational changes induced by Ca 21 /Mg 21 association to DREAM. Our data indicate a minor impact of Ca 21 association on the overall structure of the Nand C-terminal domains, although Ca 21 binding decreases the conformational heterogeneity as evident from the decrease in the fluorescence lifetime distribution in the Ca 21 bound forms of the protein. Time-resolved fluorescence data indicate that Ca 21 binding triggers a conformational transition that is characterized by more efficient quenching of Trp residue. The unfolding of DREAM occurs through an partially unfolded intermediate that is stabilized by Ca 21 association to EF-hand 3 and EF-hand 4. The native state is stabilized with respect to the partially unfolded state only in the presence of both Ca 21 and Mg 21 suggesting that, under physiological conditions, Ca 21 free DREAM exhibits a high conformational flexibility that may facilitate its physiological functions.

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“…Magnesium is not normally considered a regulator, but recent in vivo measurements have detected changes in free Mg 2ϩ concentrations in cortical neurons after treatment with neurotransmitter (25). Other NCS proteins such as GCAPs, VILIP, and NCS-1 also bind Mg 2ϩ and exhibit Mg 2ϩ -induced effects (26,27 (10). The recombinant DREAM-C protein was expressed in soluble form and could be purified in milligram amounts, in contrast to the recombinant full-length protein, which appeared insoluble in bacterial extracts.…”

Section: Dreammentioning

confidence: 99%