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PreprintCited by 9Protein Structure and DynamicsGenomics and Chromatin DynamicsDiffusion and Search Dynamics

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Intrinsically disordered regions in the transcription factor MYC:MAX modulate DNA binding via intramolecular interactions

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Schütz, Stefan, Bergsdorf, Christian, Hänni-Holzinger, Sandra, Lingel, Andreas, Renatus, Martin, Gossert, Alvar D., Jahnke, Wolfgang·2023·Biochemistry
DOI 10.1101/2023.06.21.545551

Preprint — published as 10.1021/acs.biochem.3c00608 · Paper page

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Abstract

The basic helix-loop-helix leucine zipper (bHLH-LZ) transcription factor (TF) MYC is in large parts an intrinsically disordered oncoprotein. In complex with its obligate heterodimerization partner MAX, MYC preferentially binds E-Box DNA sequences (CANNTG). At promotors containing these sequence motifs, MYC controls fundamental cellular processes such as cell cycle progression, metabolism, and apoptosis. A vast network of proteins controls MYC function via intermolecular interactions. In this work, we establish another layer of MYC regulation by intramolecular interactions. We use Nuclear Magnetic Resonance (NMR) spectroscopy to identify and map multiple binding sites for the C-terminal MYC:MAX DNA binding domain (DBD) on the intrinsically disordered regions (IDRs) in the MYC N-terminus. We find that these binding events in trans are driven by electrostatic attraction, that they have distinct affinities, and that they are competitive with DNA binding. Thereby, we observe the strongest effects for the N-terminal MYC box 0 (Mb0), a conserved motif involved in MYC transactivation and target gene induction. We prepared recombinant full-length MYC:MAX complex and demonstrate that the interactions identified in this work are also relevant in cis , i.e. as intramolecular interactions. These findings are supported by Surface Plasmon Resonance (SPR) experiments, which revealed that intramolecular IDR:DBD interactions in MYC decelerate the association of MYC:MAX complexes to DNA. Our work offers new insights how bHLH-LZ TFs are regulated by intramolecular interactions, which opens up new possibilities for drug discovery.

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Research works printed but not linked: 86

  1. Whitfield, J. R. , Beaulieu, M. E. , and Soucek, L. (2017) Strategies to inhibit Myc and their clinical applicability. Front Cell Dev Biol 5. · DOI
  2. 10.1038/nrc2231 · DOI · Paper page
  3. Madden, S. K. , de Araujo, A. D. , Gerhardt, M. , Fairlie, D. P. , and Mason, J. M. (2021) Taking the Myc out of cancer: toward therapeutic strategies to directly inhibit c-Myc. Mol Cancer 20. · DOI
  4. Whitfield, J. R. , and Soucek, L. (2021) The long journey to bring a myc inhibitor to the clinic. J. Cell Biol. 220. · DOI
  5. 10.1038/nrm1703 · DOI
  6. 1998, The role of c-myc in cellular growth control, Oncogene, 18, 2988
  7. 1999, Control of Cell Proliferation by Myc Family Genes, Mol. Cells, 9, 1, 10.1016/S1016-8478(23)13499-6 · DOI
  8. 10.1016/S0092-8674(02)00738-9 · DOI
  9. 10.1038/nature13537 · DOI
  10. 10.1073/pnas.1903432116 · DOI
  11. 1993, The c-Myc protein induces cell cycle progression and apoptosis through dimerization with Max, EMBO J, 12, 5083, 10.1002/j.1460-2075.1993.tb06202.x · DOI
  12. 10.1073/pnas.1208334110 · DOI
  13. 10.1101/gad.836800 · DOI
  14. 2019, Writing and erasing MYC ubiquitination and SUMOylation, Genes Dis, 6, 359, 10.1016/j.gendis.2019.05.006 · DOI
  15. 10.1038/sj.emboj.7600217 · DOI
  16. 10.1016/j.cell.2012.03.003 · DOI · Paper page
  17. 10.1073/pnas.0808042106 · DOI
  18. 10.1177/1947601910377492 · DOI
  19. 10.1146/annurev.cellbio.16.1.653 · DOI · Paper page
  20. 10.1016/j.molcel.2018.09.031 · DOI
  21. Tu, W. B. , Helander, S. , Pilstål, R. , Hickman, K. A. , Lourenco, C. , Jurisica, I. , Raught, B. , Wallner, B. , Sunnerhagen, M. , and Penn, L. Z. (2015) Myc and its interactors take shape. Biochim Biophys Acta Gene Regul Mech 469–483. · DOI
  22. Tarczewska, A. , and Greb-Markiewicz, B. (2019) The significance of the intrinsically disordered regions for the functions of the bHLH transcription factors. Int J Mol Sci 20. · DOI
  23. Beaulieu, M. E. , Castillo, F. , and Soucek, L. (2020) Structural and Biophysical Insights into the Function of the Intrinsically Disordered Myc Oncoprotein. Cells 9. · DOI
  24. Zhang, Q. , West-Osterfield, K. , Spears, E. , Li, Z. , Panaccione, A. , and Hann, S. R. (2017) MB0 and MBI are independent and distinct transactivation domains in MYC that are essential for transformation. Genes 8. · DOI
  25. 10.1158/0008-5472.CAN-05-0500 · DOI
  26. 10.1016/j.str.2015.10.010 · DOI
  27. Feris, E. J. , Hinds, J. W. , and Cole, M. D. (2019) Formation of a structurally-stable conformation by the intrinsically disordered MYC:TRRAP complex. PLoS One 14. · DOI · Paper page
  28. 10.1126/science.2006410 · DOI
  29. 10.1016/S0092-8674(02)01284-9 · DOI · Paper page
  30. 2019, 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, 58, 3144, 10.1021/acs.biochem.9b00296 · DOI
  31. 10.1101/gad.6.1.81 · DOI
  32. 10.1021/bi0500729 · DOI
  33. 2009, The Max homodimeric b-HLH-LZ significantly interferes with the specific heterodimerization between the c-Myc and Max b-HLH-LZ in absence of DNA: A quantitative analysis, J Mol Recognit, 22, 261, 10.1002/jmr.938 · DOI
  34. 10.1006/jmbi.1998.1914 · DOI
  35. 10.1021/bi050206i · DOI
  36. 10.1038/363038a0 · DOI
  37. 10.1128/MCB.24.10.4294-4308.2004 · DOI
  38. 10.1126/science.2251503 · DOI
  39. 10.1073/pnas.88.10.4323 · DOI
  40. 10.1093/nar/21.23.5372 · DOI
  41. 10.1073/pnas.90.3.960 · DOI
  42. Allevato, M. , Bolotin, E. , Grossman, M. , Mane-Padros, D. , Sladek, F. M. , and Martinez, E. (2017) Sequence-specific DNA binding by MYC/MAX to low-affinity non-E-box motifs. PLoS One 12. · DOI · Paper page
  43. Guo, J. , Li, T. , Schipper, J. , Nilson, K. A. , Fordjour, F. K. , Cooper, J. J. , Gordân, R. , and Price, D. H. (2014) Sequence specificity incompletely defines the genome-wide occupancy of Myc. Genome Biol 15. · DOI
  44. 2023, Multifunctional Intrinsically Disordered Regions in Transcription Factors, Chem. Eur. J, 29, e202203369, 10.1002/chem.202203369 · DOI
  45. 10.1039/c1mb05273j · DOI
  46. 2021, A phosphorylation-dependent switch in the disordered p53 transactivation domain regulates DNA binding, Proc Natl Acad Sci U S A, 118, e2021456118, 10.1073/pnas.2021456118 · DOI
  47. 10.1126/science.1111915 · DOI · Paper page
  48. 2021, Dynamic Autoinhibition of the HMGB1 Protein via Electrostatic Fuzzy Interactions of Intrinsically Disordered Regions: Dynamic Autoinhibition of HMGB1, J Mol Biol, 433, 167122, 10.1016/j.jmb.2021.167122 · DOI
  49. Engler, C. , Kandzia, R. , and Marillonnet, S. (2008) A one pot, one step, precision cloning method with high throughput capability. PLoS One 3. · DOI
  50. 2022, The Disordered MAX N-terminus Modulates DNA Binding of the Transcription Factor MYC:MAX, J Mol Biol, 434, 167833, 10.1016/j.jmb.2022.167833 · DOI
  51. 10.1073/pnas.94.23.12366 · DOI
  52. 10.1016/S0079-6565(98)00025-9 · DOI
  53. 10.1007/s10858-009-9395-y · DOI
  54. 10.1006/jmbi.1999.3034 · DOI
  55. 10.1007/s10858-007-9197-z · DOI
  56. 10.1016/j.pnmrs.2013.02.001 · DOI
  57. 10.1007/s10858-016-0060-y · DOI
  58. 10.1016/j.bbrc.2005.06.088 · DOI
  59. 10.1016/j.pep.2003.11.021 · DOI
  60. 10.1006/jmbi.2001.4537 · DOI
  61. 2023, Targeting MYC with modular synthetic transcriptional repressors derived from bHLH DNA-binding domains, Nat Biotechnol, 41, 541, 10.1038/s41587-022-01504-x · DOI
  62. 10.1093/nar/gks263 · DOI
  63. 10.1073/pnas.0402770101 · DOI
  64. 10.1038/onc.2016.354 · DOI · Paper page
  65. 10.1021/ja202259a · DOI
  66. 10.1073/pnas.1814051115 · DOI
  67. 10.1074/jbc.M110.128413 · DOI
  68. 10.1016/j.jmb.2008.09.025 · DOI
  69. 2021, Multiple regulatory intrinsically disordered motifs control FOXO4 transcription factor binding and function, Cell Rep, 36, 109446, 10.1016/j.celrep.2021.109446 · DOI
  70. 2018, The structure of INI1/hSNF5 RPT1 and its interactions with the c-MYC:MAX heterodimer provide insights into the interplay between MYC and the SWI/SNF chromatin remodeling complex, FEBS Journal, 285, 4165, 10.1111/febs.14660 · DOI
  71. Lorenzin, F. , Benary, U. , Baluapuri, A. , Walz, S. , Anna Jung, L. , von Eyss, B. , Kisker, C. , Wolf, J. , Eilers, M. , and Wolf, E. (2016) Different promoter affinities account for specificity in MYC-dependent gene regulation. Elife 15161. · DOI
  72. 10.1073/pnas.2006382117 · DOI
  73. 10.1016/j.bpj.2017.04.017 · DOI
  74. 2023, Cooperation between bHLH transcription factors and histones for DNA access, Nature, 619, 385, 10.1038/s41586-023-06282-3 · DOI
  75. 10.15252/embj.2020105464 · DOI
  76. 10.1038/nrm.2017.7 · DOI
  77. 10.1126/science.aaf4382 · DOI
  78. 10.1016/j.cell.2018.10.042 · DOI · Paper page
  79. 10.1038/s41586-022-05469-4 · DOI
  80. 10.1038/s41556-020-0485-0 · DOI
  81. 10.1126/sciadv.abd3568 · DOI
  82. Yang, J. , Chung, C.-I. , Koach, J. , Liu, H. , Navalkar, A. , Zhao, Q. , Yang, X. , He, L. , Mittag, T. , Shen, Y. , Weiss, W. A. , and Shu, X. (2023) Phase separation of Myc differentially modulates the transcriptome. bioRxiv. · DOI
  83. 10.1016/j.jmb.2022.167660 · DOI
  84. 2023, Negatively charged, intrinsically disordered regions can accelerate target search by DNA-binding proteins, Nucleic Acids Res, 51, 4701, 10.1093/nar/gkad045 · DOI
  85. 10.1021/bi0522551 · DOI
  86. 10.1073/pnas.94.23.12274 · DOI

Metadata

Authors
Schütz, S., Bergsdorf, C., Hänni-Holzinger, S., Lingel, A., Renatus, M., Gossert, A. D., & Jahnke, W.
Affiliations
  • Novartis (Switzerland) (CH)
  • ETH Zurich (CH)
Corresponding author
Jahnke, Wolfgang
ORCID
Venue
Biochemistry
Publisher
openRxiv
Published
2023-06-22
ISSN
0006-2960 (ISSN-L)
DOI
10.1101/2023.06.21.545551
OpenAlex
W4391169418
Cited by
9
References
1
Citations by year
2026: 5 · 2025: 2 · 2024: 2
FWCI
1.23
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Biochemistry (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Diffusion and Search Dynamics
Keywords
c-Myc, Max, intrinsically disordered regions, DNA binding, intramolecular interactions, E-box, electrostatic interactions, transcriptional regulation, Myc oncoprotein, drug discovery

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