ArticleThe Journal of biological chemistry2018
Myc phosphorylation in its basic helix-loop-helix region destabilizes transient α-helical structures, disrupting Max and DNA binding.
Article in The Journal of biological chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 49 citations in OpenAlex.
- Beyond the structure-function paradigm: A comprehensive review of intrinsically disordered proteins.Biochemistry and biophysics reports · 2026Review
- Gene Expression and Immunohistochemical Analyses of c-Myc in Canine and Feline Soft Tissue Fibrosarcomas.Animals : an open access journal from MDPI · 2026Article
- Article
- Beyond small molecules: advancing MYC-targeted cancer therapies through protein engineering.Transcription · 2025Review
- Regulation of Cancer Metastasis by PAK2.International journal of molecular sciences · 2024Review
- Exploring the dynamics and interactions of the N-myc transactivation domain through solution nuclear magnetic resonance spectroscopy.The Biochemical journal · 2024Article
- Article
- Bromodomain Protein-directed Agents and MYC in Small Cell Lung Cancer.Current cancer drug targets · 2024Review
- NMR-identification of the interaction between BRCA1 and the intrinsically disordered monomer of the Myc-associated factor X.Protein science : a publication of the Protein Society · 2024Article
- Visualizing single-molecule conformational transition and binding dynamics of intrinsically disordered proteins.Nature communications · 2023Article
- Review
- When Just One Phosphate Is One Too Many: The Multifaceted Interplay between Myc and Kinases.International journal of molecular sciences · 2023Review
- Genome-wide identification and characterisation of bHLH transcription factors in Artemisia annua.BMC plant biology · 2023Article
- CK2 promotes jasmonic acid signaling response by phosphorylating MYC2 in Arabidopsis.Nucleic acids research · 2023Article
- Portability of a Small-Molecule Binding Site between Disordered Proteins.Biomolecules · 2022Article
- Dynamic Control of Signaling by Phosphorylation of PDZ Binding Motifs.Methods in molecular biology (Clifton, N.J.) · 2021Article
- How to assess the structural dynamics of transcription factors by integrating sparse NMR and EPR constraints with molecular dynamics simulations.Computational and structural biotechnology journal · 2021Review
- A Switch between Two Intrinsically Disordered Conformational Ensembles Modulates the Active Site of a Basic-Helix-Loop-Helix Transcription Factor.The journal of physical chemistry letters · 2020Article
- Structural and Biophysical Insights into the Function of the Intrinsically Disordered Myc Oncoprotein.Cells · 2020Review
- Crystal Structures and Nuclear Magnetic Resonance Studies of the Apo Form of the c-MYC:MAX bHLHZip Complex Reveal a Helical Basic Region in the Absence of DNA.Biochemistry · 2019Article
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Myelocytomatosis proto-oncogene transcription factor (Myc) is an intrinsically disordered protein with critical roles in cellular homeostasis and neoplastic transformation. It is tightly regulated in the cell, with Myc phosphorylation playing a major role. In addition to the well-described tandem phosphorylation of Thr-52 and Ser-62 in the Myc transactivation domain linked to its degradation, P21 (RAC1)-activated kinase 2 (PAK2)-mediated phosphorylation of serine and threonine residues in the C-terminal basic helix-loop-helix leucine zipper (bHLH-LZ) region regulates Myc transcriptional activity. Here we report that PAK2 preferentially phosphorylates Myc twice, at Thr-358 and Ser-373, with only a minor fraction being modified at the previously identified Thr-400 site. For transcriptional activity, Myc binds E-box DNA elements, requiring its heterodimerization with Myc-associated factor X (Max) via the bHLH-LZ regions. Using isothermal calorimetry (ITC), we found that Myc phosphorylation destabilizes this ternary protein-DNA complex by decreasing Myc's affinity for Max by 2 orders of magnitude, suggesting a major effect of phosphorylation on this complex. Phosphomimetic substitutions revealed that Ser-373 dominates the effect on Myc-Max heterodimerization. Moreover, a T400D substitution disrupted Myc's affinity for Max. ITC, NMR, and CD analyses of several Myc variants suggested that the effect of phosphorylation on the Myc-Max interaction is caused by secondary structure disruption during heterodimerization rather than by a change in the structurally disordered state of Myc or by phosphorylation-induced electrostatic repulsion in the heterodimer. Our findings provide critical insights into the effects of PAK2-catalyzed phosphorylation of Myc on its interactions with Max and DNA.
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