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Calcium/calmodulin inhibition of basic-helix-loop-helix transcription factor domains

Abstract

THE ubiquitous Ca2+-binding protein calmodulin (CaM) is a key protein in Ca2+ homeostasis and activation of eukaryotic cells. CaM is the molecular link between free Ca2+ in the cell and the inhibition, or activation, of numerous enzymes. Many nuclear functions are under Ca2+/CaM control, and some transcriptional activators are known to be Ca2+ modulated indirectly through Ca2+/CaM-dependent protein kinases1–4. But Ca2+/CaM has not yet been found to directly modulate any transcription factor or other DNA-binding protein. Transcription factors of the basic-helix-loop-helix (bHLH) group are important regulators in numerous systems5–11. Here we report that binding of Ca2+-loaded CaM to the bHLH domains of several bHLH proteins directly inhibits their DNA binding. Other bHLH proteins are either less sensitive or resistant. Ca2+ ionophore selectively inhibits transcriptional activation by Ca2+/CaM-sensitive bHLH proteins in vivo, implying that Ca2+ can directly influence transcription through differential CaM inhibition of bHLH domains.

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Corneliussen, B., Holm, M., Waltersson, Y. et al. Calcium/calmodulin inhibition of basic-helix-loop-helix transcription factor domains. Nature 368, 760–764 (1994). https://doi.org/10.1038/368760a0

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