Formation of a structurally-stable conformation by the intrinsically disordered MYC:TRRAP complex


Autoři: Edmond J. Feris aff001;  John W. Hinds aff001;  Michael D. Cole aff001
Působiště autorů: Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth College, Hanover, NH, United States of America aff001;  Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States of America aff002
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225784

Souhrn

Our primary goal is to therapeutically target the oncogenic transcription factor MYC to stop tumor growth and cancer progression. Here, we report aspects of the biophysical states of the MYC protein and its interaction with one of the best-characterized MYC cofactors, TRansactivation/tRansformation-domain Associated Protein (TRRAP). The MYC:TRRAP interaction is critical for MYC function in promoting cancer. The interaction between MYC and TRRAP occurs at a precise region in the MYC protein, called MYC Homology Box 2 (MB2), which is central to the MYC transactivation domain (TAD). Although the MYC TAD is inherently disordered, this report suggests that MB2 may acquire a defined structure when complexed with TRRAP which could be exploited for the investigation of inhibitors of MYC function by preventing this protein-protein interaction (PPI). The MYC TAD, and in particular the MB2 motif, is unique and invariant in evolution, suggesting that MB2 is an ideal site for inhibiting MYC function.

Klíčová slova:

Carcinogenesis – Protein domains – Protein interactions – Protein structure – Protein structure prediction – Transcription factors – Ethylene – Glycols


Zdroje

1. Weinstein IB, Joe A, Felsher D. Oncogene Addiction. Cancer Res. 2008;68: 3077–3080. doi: 10.1158/0008-5472.CAN-07-3293 18451130

2. Bradner JE, Hnisz D, Young RA. Transcriptional Addiction in Cancer. Cell. 2017;168: 629–643. doi: 10.1016/j.cell.2016.12.013 28187285

3. Dang CV, O’Donnell KA, Zeller KI, Nguyen T, Osthus RC, Li F. The c-Myc target gene network. Semin Cancer Biol. 2006;16: 253–264. doi: 10.1016/j.semcancer.2006.07.014 16904903

4. Shachaf CM, Gentles AJ, Elchuri S, Sahoo D, Soen Y, Sharpe O, et al. Genomic and proteomic analysis reveals a threshold level of MYC required for tumor maintenance. Cancer Res. 2008;68: 5132–5142. doi: 10.1158/0008-5472.CAN-07-6192 18593912

5. Yekkala K, Baudino TA. Inhibition of intestinal polyposis with reduced angiogenesis in ApcMin/+ mice due to decreases in c-Myc expression. Mol Cancer Res MCR. 2007;5: 1296–1303. doi: 10.1158/1541-7786.MCR-07-0232 18171987

6. Meyer N, Penn LZ. Reflecting on 25 years with MYC. Nat Rev. 2008;8: 976–990. doi: 10.1038/nrc2231 19029958

7. Charron J, Malynn BA, Fisher P, Stewart V, Jeannotte L, Goff SP, et al. Embryonic lethality in mice homozygous for a targeted disruption of the N-myc gene. Genes Dev. 1992;6: 2248–2257. doi: 10.1101/gad.6.12a.2248 1459450

8. Knoepfler PS, Cheng PF, Eisenman RN. N-myc is essential during neurogenesis for the rapid expansion of progenitor cell populations and the inhibition of neuronal differentiation. Genes Dev. 2002;16: 2699–2712. doi: 10.1101/gad.1021202 12381668

9. Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, et al. The landscape of somatic copy-number alteration across human cancers. Nature. 2010;463: 899–905. doi: 10.1038/nature08822 20164920

10. Dang CV. MYC on the path to cancer. Cell. 2012;149: 22–35. doi: 10.1016/j.cell.2012.03.003 22464321

11. Nair SK, Burley SK. X-ray structures of Myc-Max and Mad-Max recognizing DNA. Molecular bases of regulation by proto-oncogenic transcription factors. Cell. 2003;112: 193–205. doi: 10.1016/s0092-8674(02)01284-9 12553908

12. Brownlie P, Ceska T, Lamers M, Romier C, Stier G, Teo H, et al. The crystal structure of an intact human Max–DNA complex: new insights into mechanisms of transcriptional control. Structure. 1997;5: 509–520. doi: 10.1016/s0969-2126(97)00207-4 9115440

13. Cole MD, Cowling VH. Transcription-independent functions of MYC: regulation of translation and DNA replication. Nat Rev Mol Cell Biol. 2008;9: 810–815. doi: 10.1038/nrm2467 18698328

14. Brown SJ, Cole MD, Erives AJ. Evolution of the holozoan ribosome biogenesis regulon. BMC Genomics. 2008;9: 442. doi: 10.1186/1471-2164-9-442 18816399

15. Cowling VH, Chandriani S, Whitfield ML, Cole MD. A conserved Myc protein domain, MBIV, regulates DNA binding, apoptosis, transformation, and G2 arrest. Mol Cell Biol. 2006;26: 4226–4239. doi: 10.1128/MCB.01959-05 16705173

16. McKeown MR, Bradner JE. Therapeutic strategies to inhibit MYC. Cold Spring Harb Perspect Med. 2014;4. doi: 10.1101/cshperspect.a014266 25274755

17. Nikiforov MA, Chandriani S, Park J, Kotenko I, Matheos D, Johnsson A, et al. TRRAP-dependent and TRRAP-independent transcriptional activation by Myc family oncoproteins. Mol Cell Biol. 2002;22: 5054–5063. doi: 10.1128/MCB.22.14.5054-5063.2002 12077335

18. Carabet LA, Rennie PS, Cherkasov A. Therapeutic Inhibition of Myc in Cancer. Structural Bases and Computer-Aided Drug Discovery Approaches. Int J Mol Sci. 2018;20. doi: 10.3390/ijms20010120 30597997

19. Posternak V, Cole MD. Strategically targeting MYC in cancer. F1000Research. 2016;5. doi: 10.12688/f1000research.7879.1 27081479

20. Whitfield JR, Beaulieu M-E, Soucek L. Strategies to Inhibit Myc and Their Clinical Applicability. Front Cell Dev Biol. 2017;5: 10. doi: 10.3389/fcell.2017.00010 28280720

21. Brough DE, Hofmann TJ, Ellwood KB, Townley RA, Cole MD. An essential domain of the c-myc protein interacts with a nuclear factor that is also required for E1A-mediated transformation. Mol Cell Biol. 1995;15: 1536–1544. doi: 10.1128/mcb.15.3.1536 7862146

22. Cowling VH, Cole MD. Mechanism of transcriptional activation by the Myc oncoproteins. Semin Cancer Biol. 2006;16: 242–252. doi: 10.1016/j.semcancer.2006.08.001 16935524

23. McMahon SB, Van Buskirk HA, Dugan KA, Copeland TD, Cole MD. The novel ATM-related protein TRRAP is an essential cofactor for the c-Myc and E2F oncoproteins. Cell. 1998;94: 363–374. doi: 10.1016/s0092-8674(00)81479-8 9708738

24. Kalkat M, Resetca D, Lourenco C, Chan P-K, Wei Y, Shiah Y-J, et al. MYC Protein Interactome Profiling Reveals Functionally Distinct Regions that Cooperate to Drive Tumorigenesis. Mol Cell. 2018;72: 836–848.e7. doi: 10.1016/j.molcel.2018.09.031 30415952

25. Murr R, Vaissière T, Sawan C, Shukla V, Herceg Z. Orchestration of chromatin-based processes: mind the TRRAP. Oncogene. 2007;26: 5358–5372. doi: 10.1038/sj.onc.1210605 17694078

26. Baretić D, Williams RL. PIKKs—the solenoid nest where partners and kinases meet. Curr Opin Struct Biol. 2014;29: 134–142. doi: 10.1016/j.sbi.2014.11.003 25460276

27. Lempiäinen H, Halazonetis TD. Emerging common themes in regulation of PIKKs and PI3Ks. EMBO J. 2009;28: 3067–3073. doi: 10.1038/emboj.2009.281 19779456

28. Saleh A, Schieltz D, Ting N, McMahon SB, Litchfield DW, Yates JR, et al. Tra1p is a component of the yeast Ada.Spt transcriptional regulatory complexes. J Biol Chem. 1998;273: 26559–26565. doi: 10.1074/jbc.273.41.26559 9756893

29. Doyon Y, Côté J. The highly conserved and multifunctional NuA4 HAT complex. Curr Opin Genet Dev. 2004;14: 147–154. doi: 10.1016/j.gde.2004.02.009 15196461

30. Grant PA, Schieltz D, Pray-Grant MG, Yates JR, Workman JL. The ATM-related cofactor Tra1 is a component of the purified SAGA complex. Mol Cell. 1998;2: 863–867. doi: 10.1016/s1097-2765(00)80300-7 9885573

31. Herceg Z, Hulla W, Gell D, Cuenin C, Lleonart M, Jackson S, et al. Disruption of Trrap causes early embryonic lethality and defects in cell cycle progression. Nat Genet. 2001;29: 206–211. doi: 10.1038/ng725 11544477

32. Murugan AK, Yang C, Xing M. Mutational analysis of the GNA11, MMP27, FGD1, TRRAP and GRM3 genes in thyroid cancer. Oncol Lett. 2013;6: 437–441. doi: 10.3892/ol.2013.1391 24137342

33. Wei X, Walia V, Lin JC, Teer JK, Prickett TD, Gartner J, et al. Exome sequencing identifies GRIN2A as frequently mutated in melanoma. Nat Genet. 2011;43: 442–446. doi: 10.1038/ng.810 21499247

34. McMahon SB, Wood MA, Cole MD. The essential cofactor TRRAP recruits the histone acetyltransferase hGCN5 to c-Myc. Mol Cell Biol. 2000;20: 556–562. doi: 10.1128/mcb.20.2.556-562.2000 10611234

35. Brown CE, Howe L, Sousa K, Alley SC, Carrozza MJ, Tan S, et al. Recruitment of HAT complexes by direct activator interactions with the ATM-related Tra1 subunit. Science. 2001;292: 2333–2337. doi: 10.1126/science.1060214 11423663

36. Ard PG, Chatterjee C, Kunjibettu S, Adside LR, Gralinski LE, McMahon SB. Transcriptional regulation of the mdm2 oncogene by p53 requires TRRAP acetyltransferase complexes. Mol Cell Biol. 2002;22: 5650–5661. doi: 10.1128/MCB.22.16.5650-5661.2002 12138177

37. Lang SE, Hearing P. The adenovirus E1A oncoprotein recruits the cellular TRRAP/GCN5 histone acetyltransferase complex. Oncogene. 2003;22: 2836–2841. doi: 10.1038/sj.onc.1206376 12743606

38. Das C, Tyler JK. Histone exchange and histone modifications during transcription and aging. Biochim Biophys Acta. 2013;1819: 332–342. doi: 10.1016/j.bbagrm.2011.08.001 24459735

39. Park J, Kunjibettu S, McMahon SB, Cole MD. The ATM-related domain of TRRAP is required for histone acetyltransferase recruitment and Myc-dependent oncogenesis. Genes Dev. 2001;15: 1619–1624. doi: 10.1101/gad.900101 11445536

40. Díaz-Santín LM, Lukoyanova N, Aciyan E, Cheung AC. Cryo-EM structure of the SAGA and NuA4 coactivator subunit Tra1 at 3.7 angstrom resolution. eLife. 2017;6. doi: 10.7554/eLife.28384 28767037

41. Knutson BA, Hahn S. Domains of Tra1 important for activator recruitment and transcription coactivator functions of SAGA and NuA4 complexes. Mol Cell Biol. 2011;31: 818–831. doi: 10.1128/MCB.00687-10 21149579

42. Lee W, Cornilescu G, Dashti H, Eghbalnia HR, Tonelli M, Westler WM, et al. Integrative NMR for biomolecular research. J Biomol NMR. 2016;64: 307–332. doi: 10.1007/s10858-016-0029-x 27023095

43. McEwan IJ, Dahlman-Wright K, Ford J, Wright AP. Functional interaction of the c-Myc transactivation domain with the TATA binding protein: evidence for an induced fit model of transactivation domain folding. Biochemistry. 1996;35: 9584–9593. doi: 10.1021/bi960793v 8755740

44. Tu WB, Helander S, Pilstål R, Hickman KA, Lourenco C, Jurisica I, et al. Myc and its interactors take shape. Biochim Biophys Acta BBA—Gene Regul Mech. 2015;1849: 469–483. doi: 10.1016/j.bbagrm.2014.06.002 24933113

45. Krois AS, Ferreon JC, Martinez-Yamout MA, Dyson HJ, Wright PE. Recognition of the disordered p53 transactivation domain by the transcriptional adapter zinc finger domains of CREB-binding protein. Proc Natl Acad Sci. 2016;113: E1853–E1862. doi: 10.1073/pnas.1602487113 26976603

46. Chen X, Zaro JL, Shen W-C. Fusion protein linkers: property, design and functionality. Adv Drug Deliv Rev. 2013;65: 1357–1369. doi: 10.1016/j.addr.2012.09.039 23026637

47. Lee W, Kim JH, Westler WM, Markley JL. PONDEROSA, an automated 3D-NOESY peak picking program, enables automated protein structure determination. Bioinformatics. 2011;27: 1727–1728. doi: 10.1093/bioinformatics/btr200 21511715

48. Neidigh JW, Fesinmeyer RM, Prickett KS, Andersen NH. Exendin-4 and glucagon-like-peptide-1: NMR structural comparisons in the solution and micelle-associated states. Biochemistry. 2001;40: 13188–13200. doi: 10.1021/bi010902s 11683627

49. Upadhyay V, Singh A, Jha D, Singh A, Panda AK. Recovery of bioactive protein from bacterial inclusion bodies using trifluoroethanol as solubilization agent. Microb Cell Factories. 2016;15: 100. doi: 10.1186/s12934-016-0504-9 27277580

50. Sonnichsen FD, Van Eyk JE, Hodges RS, Sykes BD. Effect of trifluoroethanol on protein secondary structure: an NMR and CD study using a synthetic actin peptide. Biochemistry. 1992;31: 8790–8798. doi: 10.1021/bi00152a015 1390666

51. Gast K, Zirwer D, Müller-Frohne M, Damaschun G. Trifluoroethanol-induced conformational transitions of proteins: Insights gained from the differences between α-lactalbumin and ribonuclease A. Protein Sci. 2008;8: 625–634. doi: 10.1110/ps.8.3.625 10091665

52. Felsher DW. MYC Inactivation Elicits Oncogene Addiction through Both Tumor Cell-Intrinsic and Host-Dependent Mechanisms. Genes Cancer. 2010;1: 597–604. doi: 10.1177/1947601910377798 21037952

53. Fiorentino FP, Tokgün E, Solé-Sánchez S, Giampaolo S, Tokgün O, Jauset T, et al. Growth suppression by MYC inhibition in small cell lung cancer cells with TP53 and RB1 inactivation. Oncotarget. 2016;7: 31014–31028. doi: 10.18632/oncotarget.8826 27105536

54. Soucek L, Whitfield JR, Sodir NM, Massó-Vallés D, Serrano E, Karnezis AN, et al. Inhibition of Myc family proteins eradicates KRas-driven lung cancer in mice. Genes Dev. 2013;27: 504–513. doi: 10.1101/gad.205542.112 23475959

55. Wang X, Ahmad S, Zhang Z, Côté J, Cai G. Architecture of the Saccharomyces cerevisiae NuA4/TIP60 complex. Nat Commun. 2018;9: 1147. doi: 10.1038/s41467-018-03504-5 29559617

56. Rivera-Calzada A, López-Perrote A, Melero R, Boskovic J, Muñoz-Hernández H, Martino F, et al. Structure and Assembly of the PI3K-like Protein Kinases (PIKKs) Revealed by Electron Microscopy. AIMS Biophys. 2015;2: 36–57. doi: 10.3934/biophy.2015.2.36

57. Sibanda BL, Chirgadze DY, Ascher DB, Blundell TL. DNA-PKcs structure suggests an allosteric mechanism modulating DNA double-strand break repair. Science. 2017;355: 520–524. doi: 10.1126/science.aak9654 28154079

58. Daub H, Olsen JV, Bairlein M, Gnad F, Oppermann FS, Körner R, et al. Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. Mol Cell. 2008;31: 438–448. doi: 10.1016/j.molcel.2008.07.007 18691976

59. Dephoure N, Zhou C, Villén J, Beausoleil SA, Bakalarski CE, Elledge SJ, et al. A quantitative atlas of mitotic phosphorylation. Proc Natl Acad Sci U S A. 2008;105: 10762–10767. doi: 10.1073/pnas.0805139105 18669648

60. Zhou H, Di Palma S, Preisinger C, Peng M, Polat AN, Heck AJR, et al. Toward a comprehensive characterization of a human cancer cell phosphoproteome. J Proteome Res. 2013;12: 260–271. doi: 10.1021/pr300630k 23186163

61. Allard S, Utley RT, Savard J, Clarke A, Grant P, Brandl CJ, et al. NuA4, an essential transcription adaptor/histone H4 acetyltransferase complex containing Esa1p and the ATM-related cofactor Tra1p. EMBO J. 1999;18: 5108–5119. doi: 10.1093/emboj/18.18.5108 10487762

62. Grant PA, Duggan L, Côté J, Roberts SM, Brownell JE, Candau R, et al. Yeast Gcn5 functions in two multisubunit complexes to acetylate nucleosomal histones: characterization of an Ada complex and the SAGA (Spt/Ada) complex. Genes Dev. 1997;11: 1640–1650. doi: 10.1101/gad.11.13.1640 9224714

63. Côté J, Utley RT, Workman JL. [6] Basic analysis of transcription factor binding to nucleosomes. Methods in Molecular Genetics. Elsevier; 1995. pp. 108–128. doi: 10.1016/S1067-2389(06)80009-9

64. Drozdetskiy A, Cole C, Procter J, Barton GJ. JPred4: a protein secondary structure prediction server. Nucleic Acids Res. 2015;43: W389–W394. doi: 10.1093/nar/gkv332 25883141


Článek vyšel v časopise

PLOS One


2019 Číslo 12