NMR Structure of DREAM: Implications for Ca<sup>2+</sup>-Dependent DNA Binding and Protein Dimerization

Lusin, Jacqueline D.; Vanarotti, Murugendra; Dace, Alexandra; Li, Congmin; Valiveti, Aswani; Ames, James B.

doi:10.1021/bi800763a

Cited by 7 publications

(29 citation statements)

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“…Different from the KChIP1 structure (PDB ID 1S1E), the KChIP3 EF3-4 structure (PDB ID 2E6W) showed a disordered long loop connecting EF-hands 3 and 4, which, due to its flexibility, is thought to function as fingers during calcium signaling or other molecules’ binding and recognition. In 2008, Lusin et al determined another solution NMR structure of KChIP3 (PDB ID 2JUL) [ 51 ]. This NMR KChIP3 structure unveiled a similar overall folding as KChIP1 (PDB ID 1S1E).…”

Section: Potassium Channel Interacting Proteins (Kchips)mentioning

confidence: 99%

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Pharmacological Approaches for the Modulation of the Potassium Channel KV4.x and KChIPs

Cercós

Peraza

Benito-Bueno

et al. 2021

IJMS

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Ion channels are macromolecular complexes present in the plasma membrane and intracellular organelles of cells. Dysfunction of ion channels results in a group of disorders named channelopathies, which represent an extraordinary challenge for study and treatment. In this review, we will focus on voltage-gated potassium channels (KV), specifically on the KV4-family. The activation of these channels generates outward currents operating at subthreshold membrane potentials as recorded from myocardial cells (ITO, transient outward current) and from the somata of hippocampal neurons (ISA). In the heart, KV4 dysfunctions are related to Brugada syndrome, atrial fibrillation, hypertrophy, and heart failure. In hippocampus, KV4.x channelopathies are linked to schizophrenia, epilepsy, and Alzheimer’s disease. KV4.x channels need to assemble with other accessory subunits (β) to fully reproduce the ITO and ISA currents. β Subunits affect channel gating and/or the traffic to the plasma membrane, and their dysfunctions may influence channel pharmacology. Among KV4 regulatory subunits, this review aims to analyze the KV4/KChIPs interaction and the effect of small molecule KChIP ligands in the A-type currents generated by the modulation of the KV4/KChIP channel complex. Knowledge gained from structural and functional studies using activators or inhibitors of the potassium current mediated by KV4/KChIPs will better help understand the underlying mechanism involving KV4-mediated-channelopathies, establishing the foundations for drug discovery, and hence their treatments.

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Section: Potassium Channel Interacting Proteins (Kchips)mentioning

confidence: 99%

“… Three-dimensional structures of free KChIPs. The four EF-hand motifs are shown, as representative examples: ( A ) KChIP3 (PDB ID 2JUL) [ 51 ] and ( B ) KChIP4a (PDB ID 3DD4) [ 52 ]. Different from KChIP1-3, KChIP4a C-terminal α-helix H10 (red) swings outward at ~45° from the hydrophobic pocket.…”

Section: Figurementioning

confidence: 99%

Pharmacological Approaches for the Modulation of the Potassium Channel KV4.x and KChIPs

Cercós

Peraza

Benito-Bueno

et al. 2021

IJMS

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“…Mg 2+ ions bind to the second EF-hand domain, and this interaction is critical in allowing DREAM to bind to DNA (Osawa et al 2005). High levels of intracellular Ca 2+ result in Ca 2+ binding to the third and fourth EF-hand domains (Lusin et al 2008). Ca 2+ binding promotes the formation of DREAM homodimers, which are unable to interact with DRE sequences, resulting in transcriptional derepression (Lusin et al 2008).…”

Section: Molecular and Cellular Functionsmentioning

confidence: 99%

“…High levels of intracellular Ca 2+ result in Ca 2+ binding to the third and fourth EF-hand domains (Lusin et al 2008). Ca 2+ binding promotes the formation of DREAM homodimers, which are unable to interact with DRE sequences, resulting in transcriptional derepression (Lusin et al 2008). DREAM recognizes and binds to the consensus DRE sequence 3 0 -PuNGTCAPuPuG-5 0 (Carrión et al 1998).…”

Section: Molecular and Cellular Functionsmentioning

confidence: 99%

“…The molecular functions of DREAM/KChIP3/ calsenilin are dependent on specific structural properties of the protein as well as posttranslational modifications. For example, there are numerous positively charged amino acid side chains (K87, K90, K91, R98, K101, R60, and K166) that are clustered on one aspect of the protein surface that may mediate electrostatic interactions with target DNAs (Lusin et al 2008). Nuclear localization of DREAM appears to depend on its sumoylation by the SUMO-conjugating enzyme UBC9 at two specific residues, lys-26 and lys-90 (Palczewska et al 2011).…”

Section: Molecular and Cellular Functionsmentioning

confidence: 99%

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Dbf4

Masai¹

2018

Encyclopedia of Signaling Molecules

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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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NMR Structure of DREAM: Implications for Ca²⁺-Dependent DNA Binding and Protein Dimerization

Cited by 7 publications

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Pharmacological Approaches for the Modulation of the Potassium Channel KV4.x and KChIPs

Pharmacological Approaches for the Modulation of the Potassium Channel KV4.x and KChIPs

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

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NMR Structure of DREAM: Implications for Ca2+-Dependent DNA Binding and Protein Dimerization

Cited by 7 publications

References 0 publications

Pharmacological Approaches for the Modulation of the Potassium Channel KV4.x and KChIPs

Pharmacological Approaches for the Modulation of the Potassium Channel KV4.x and KChIPs

Dbf4

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

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NMR Structure of DREAM: Implications for Ca²⁺-Dependent DNA Binding and Protein Dimerization

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