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Extended string binding mode of the phosphorylated transactivation domain of tumor suppressor p53.

Okuda M, Nishimura Y
J Am Chem Soc 136 14143-52 (2014)
Cited: 31 times
EuropePMC logo PMID: 25216154

Abstract

The transactivation domain (TAD) of tumor suppressor p53 has homologous subdomains, TAD1 and TAD2. Both are intrinsically disordered in their free states, but all structures of TAD1 and TAD2 bound to their target proteins have demonstrated use of an amphipathic α-helix, suggesting that the binding-coupled helix folding mechanism of TAD1 and TAD2 is essential. Although phosphorylation of TAD is important to switch the function of p53, bound structures of phosphorylated TAD1 and TAD2 have not been determined. Here, we reveal the recognition mechanism of the phosphorylated TAD2 bound to a pleckstrin homology (PH) domain from human TFIIH subunit p62 in an extended string-like conformation. This string-like binding mode of TAD2 seems to be independent of its phosphorylation in spite of enhanced binding activity upon phosphorylation. This is in contrast to the amphipathic helical binding mode of the unphosphorylated TAD2 to the yeast tfb1 PH domain and demonstrates that the p53 TAD2 has much higher conformational malleability than previously appreciated.

Reviews - 2ruk mentioned but not cited (4)

  1. p53 Proteoforms and Intrinsic Disorder: An Illustration of the Protein Structure-Function Continuum Concept. Uversky VN. Int J Mol Sci 17 E1874 (2016)
  2. On the specificity of protein-protein interactions in the context of disorder. Teilum K, Olsen JG, Kragelund BB. Biochem J 478 2035-2050 (2021)
  3. Bacterial cupredoxin azurin hijacks cellular signaling networks: Protein-protein interactions and cancer therapy. Gao M, Zhou J, Su Z, Huang Y. Protein Sci 26 2334-2341 (2017)
  4. Dynamic structures of intrinsically disordered proteins related to the general transcription factor TFIIH, nucleosomes, and histone chaperones. Okuda M, Tsunaka Y, Nishimura Y. Biophys Rev 14 1449-1472 (2022)

Articles - 2ruk mentioned but not cited (8)

  1. Tumor-Suppressor p53TAD1-60 Forms a Fuzzy Complex with Metastasis-Associated S100A4: Structural Insights and Dynamics by an NMR/MD Approach. Dudás EF, Pálfy G, Menyhárd DK, Sebák F, Ecsédi P, Nyitray L, Bodor A. Chembiochem 21 3087-3095 (2020)
  2. Adaptive patterns in the p53 protein sequence of the hypoxia- and cancer-tolerant blind mole rat Spalax. Domankevich V, Opatowsky Y, Malik A, Korol AB, Frenkel Z, Manov I, Avivi A, Shams I. BMC Evol Biol 16 177 (2016)
  3. Real-time and simultaneous monitoring of the phosphorylation and enhanced interaction of p53 and XPC acidic domains with the TFIIH p62 subunit. Okuda M, Nishimura Y. Oncogenesis 4 e150 (2015)
  4. Structural and dynamical insights into the PH domain of p62 in human TFIIH. Okuda M, Ekimoto T, Kurita JI, Ikeguchi M, Nishimura Y. Nucleic Acids Res 49 2916-2930 (2021)
  5. Exploring the Molecular Mechanism of Liuwei Dihuang Pills for Treating Diabetic Nephropathy by Combined Network Pharmacology and Molecular Docking. Wang G, Zeng L, Huang Q, Lu Z, Sui R, Liu D, Zeng H, Liu X, Chu S, Kou X, Li H. Evid Based Complement Alternat Med 2021 7262208 (2021)
  6. FuzPred: a web server for the sequence-based prediction of the context-dependent binding modes of proteins. Hatos A, Teixeira JMC, Barrera-Vilarmau S, Horvath A, Tosatto SCE, Vendruscolo M, Fuxreiter M. Nucleic Acids Res 51 W198-W206 (2023)
  7. Recognizing the Binding Pattern and Dissociation Pathways of the p300 Taz2-p53 TAD2 Complex. Li T, Motta S, Stevens AO, Song S, Hendrix E, Pandini A, He Y. JACS Au 2 1935-1945 (2022)
  8. Comparative computational and experimental analyses of some natural small molecules to restore transcriptional activation function of p53 in cancer cells harbouring wild type and p53Ser46 mutant. Shefrin S, Sari AN, Kumar V, Zhang H, Meidinna HN, Kaul SC, Wadhwa R, Sundar D. Curr Res Struct Biol 4 320-331 (2022)


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  2. XPA: A key scaffold for human nucleotide excision repair. Sugitani N, Sivley RM, Perry KE, Capra JA, Chazin WJ. DNA Repair (Amst) 44 123-135 (2016)
  3. Advances in Hydrogen/Deuterium Exchange Mass Spectrometry and the Pursuit of Challenging Biological Systems. James EI, Murphree TA, Vorauer C, Engen JR, Guttman M. Chem Rev 122 7562-7623 (2022)
  4. The Transactivation Domains of the p53 Protein. Raj N, Attardi LD. Cold Spring Harb Perspect Med 7 a026047 (2017)
  5. Targeting GRK5 for Treating Chronic Degenerative Diseases. Marzano F, Rapacciuolo A, Ferrara N, Rengo G, Koch WJ, Cannavo A. Int J Mol Sci 22 1920 (2021)

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  1. Recognition of the disordered p53 transactivation domain by the transcriptional adapter zinc finger domains of CREB-binding protein. Krois AS, Ferreon JC, Martinez-Yamout MA, Dyson HJ, Wright PE. Proc Natl Acad Sci U S A 113 E1853-62 (2016)
  2. Common TFIIH recruitment mechanism in global genome and transcription-coupled repair subpathways. Okuda M, Nakazawa Y, Guo C, Ogi T, Nishimura Y. Nucleic Acids Res 45 13043-13055 (2017)
  3. Characterization of the p300 Taz2-p53 TAD2 complex and comparison with the p300 Taz2-p53 TAD1 complex. Miller Jenkins LM, Feng H, Durell SR, Tagad HD, Mazur SJ, Tropea JE, Bai Y, Appella E. Biochemistry 54 2001-2010 (2015)
  4. Structural characterization of interactions between transactivation domain 1 of the p65 subunit of NF-κB and transcription regulatory factors. Lecoq L, Raiola L, Chabot PR, Cyr N, Arseneault G, Legault P, Omichinski JG. Nucleic Acids Res 45 5564-5576 (2017)
  5. A phosphorylation-dependent switch in the disordered p53 transactivation domain regulates DNA binding. Sun X, Dyson HJ, Wright PE. Proc Natl Acad Sci U S A 118 e2021456118 (2021)
  6. A ΩXaV motif in the Rift Valley fever virus NSs protein is essential for degrading p62, forming nuclear filaments and virulence. Cyr N, de la Fuente C, Lecoq L, Guendel I, Chabot PR, Kehn-Hall K, Omichinski JG. Proc Natl Acad Sci U S A 112 6021-6026 (2015)
  7. ETV4 and AP1 Transcription Factors Form Multivalent Interactions with three Sites on the MED25 Activator-Interacting Domain. Currie SL, Doane JJ, Evans KS, Bhachech N, Madison BJ, Lau DKW, McIntosh LP, Skalicky JJ, Clark KA, Graves BJ. J Mol Biol 429 2975-2995 (2017)
  8. Structure and function of yeast Atg20, a sorting nexin that facilitates autophagy induction. Popelka H, Damasio A, Hinshaw JE, Klionsky DJ, Ragusa MJ. Proc Natl Acad Sci U S A 114 E10112-E10121 (2017)
  9. Extended string-like binding of the phosphorylated HP1α N-terminal tail to the lysine 9-methylated histone H3 tail. Shimojo H, Kawaguchi A, Oda T, Hashiguchi N, Omori S, Moritsugu K, Kidera A, Hiragami-Hamada K, Nakayama J, Sato M, Nishimura Y. Sci Rep 6 22527 (2016)
  10. Characterization of the structural ensembles of p53 TAD2 by molecular dynamics simulations with different force fields. Ouyang Y, Zhao L, Zhang Z. Phys Chem Chem Phys 20 8676-8684 (2018)
  11. Three human RNA polymerases interact with TFIIH via a common RPB6 subunit. Okuda M, Suwa T, Suzuki H, Yamaguchi Y, Nishimura Y. Nucleic Acids Res 50 1-16 (2022)
  12. Dynamics of the Extended String-Like Interaction of TFIIE with the p62 Subunit of TFIIH. Okuda M, Higo J, Komatsu T, Konuma T, Sugase K, Nishimura Y. Biophys J 111 950-962 (2016)
  13. Elf1 promotes transcription-coupled repair in yeast by using its C-terminal domain to bind TFIIH. Selvam K, Xu J, Wilson HE, Oh J, Li Q, Wang D, Wyrick JJ. Nat Commun 15 6223 (2024)
  14. Structural polymorphism of the PH domain in TFIIH. Okuda M, Nishimura Y. Biosci Rep 43 BSR20230846 (2023)


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