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2017 ; 8
(2
): 3327-3343
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Calcium-dependent binding of Myc to calmodulin
#MMPMID27926480
Raffeiner P
; Schraffl A
; Schwarz T
; Röck R
; Ledolter K
; Hartl M
; Konrat R
; Stefan E
; Bister K
Oncotarget
2017[Jan]; 8
(2
): 3327-3343
PMID27926480
show ga
The bHLH-LZ (basic region/helix-loop-helix/leucine zipper) oncoprotein Myc and
the bHLH-LZ protein Max form a binary transcription factor complex controlling
fundamental cellular processes. Deregulated Myc expression leads to neoplastic
transformation and is a hallmark of most human cancers. The dynamics of Myc
transcription factor activity are post-translationally coordinated by defined
protein-protein interactions. Here, we present evidence for a second messenger
controlled physical interaction between the Ca2+ sensor calmodulin (CaM) and all
Myc variants (v-Myc, c-Myc, N-Myc, and L-Myc). The predominantly cytoplasmic
Myc:CaM interaction is Ca2+-dependent, and the binding site maps to the conserved
bHLH domain of Myc. Ca2+-loaded CaM binds the monomeric and intrinsically
disordered Myc protein with high affinity, whereas Myc:Max heterodimers show
less, and Max homodimers no affinity for CaM. NMR spectroscopic analyses using
alternating mixtures of 15N-labeled and unlabeled preparations of CaM and a
monomeric Myc fragment containing the bHLH-LZ domain corroborate the biochemical
results on the Myc:CaM interaction and confirm the interaction site mapping. In
electrophoretic mobility shift assays, addition of CaM does not affect
high-affinity DNA-binding of Myc:Max heterodimers. However, cell-based reporter
analyses and cell transformation assays suggest that increasing CaM levels
enhance Myc transcriptional and oncogenic activities. Our results point to a
possible involvement of Ca2+ sensing CaM in the fine-tuning of Myc function.
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