Calcium/calmodulin inhibition of basic-helix-loop-helix transcription factor domains.
The ubiquitous Ca(2+)-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 kinases. 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 systems. Here we report that binding of Ca(2+)-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.
Corneliussen
B
B
Department of Applied Cell and Molecular Biology, University of Umeå, Sweden.
Holm
M
M
Waltersson
Y
Y
Onions
J
J
Hallberg
B
B
Thornell
A
A
Grundström
T
T
D000818:Animals; D001483:Base Sequence; D002118:Calcium / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002147:Calmodulin / Q000502:physiology*; D002417:Cattle; D002460:Cell Line; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology; D005976:Glutaral / Q000494:pharmacology; D018257:Helix-Loop-Helix Motifs / Q000502:physiology*; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D011485:Protein Binding; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*
D002147:Calmodulin; D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins; D014157:Transcription Factors; D015759:Ionomycin; D004247:DNA; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium; D005976:Glutaral