Extended String Binding Mode of the Phosphorylated Transactivation Domain of Tumor Suppressor p53

Okuda, Masahiko; Nishimura, Yoshifumi

doi:10.1021/ja506351f

Cited by 49 publications

(73 citation statements)

References 63 publications

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“…A similar AD2 structure is observed in the complex with HMGB1, although the helix is somewhat shorter (64). Somewhat surprisingly, given the strong propensity of AD2 to fold into a helix, a doubly phosphorylated p53 AD2 motif binds in a more extended conformation to a highly electropositive region of the PH domain of human TFIIH p62 (65).…”

Section: Discussionmentioning

confidence: 63%

Recognition of the disordered p53 transactivation domain by the transcriptional adapter zinc finger domains of CREB-binding protein

Krois

Ferreon

Martinez-Yamout

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

112

129

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An important component of the activity of p53 as a tumor suppressor is its interaction with the transcriptional coactivators cyclic-AMP response element-binding protein (CREB)-binding protein (CBP) and p300, which activate transcription of p53-regulated stress response genes and stabilize p53 against ubiquitin-mediated degradation. The highest affinity interactions are between the intrinsically disordered N-terminal transactivation domain (TAD) of p53 and the TAZ1 and TAZ2 domains of CBP/p300. The NMR spectra of simple binary complexes of the TAZ1 and TAZ2 domains with the p53TAD suffer from exchange broadening, but innovations in construct design and isotopic labeling have enabled us to obtain high-resolution structures using fusion proteins, uniformly labeled in the case of the TAZ2-p53TAD fusion and segmentally labeled through transintein splicing for the TAZ1-p53TAD fusion. The p53TAD is bipartite, with two interaction motifs, termed AD1 and AD2, which fold to form short amphipathic helices upon binding to TAZ1 and TAZ2 whereas intervening regions of the p53TAD remain flexible. Both the AD1 and AD2 motifs bind to hydrophobic surfaces of the TAZ domains, with AD2 making more extensive hydrophobic contacts consistent with its greater contribution to the binding affinity. Binding of AD1 and AD2 is synergistic, and structural studies performed with isolated motifs can be misleading. The present structures of the fulllength p53TAD complexes demonstrate the versatility of the interactions available to an intrinsically disordered domain containing bipartite interaction motifs and provide valuable insights into the structural basis of the affinity changes that occur upon stressrelated posttranslational modification.intrinsically disordered protein | binding motif | transcriptional coactivator | intein | segmental labeling

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Section: Discussionmentioning

confidence: 63%

Recognition of the disordered p53 transactivation domain by the transcriptional adapter zinc finger domains of CREB-binding protein

Krois

Ferreon

Martinez-Yamout

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

112

129

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“…In addition to XPC, the p62 PH domain binds to an acidic domain of the general transcription factor TFIIEa Okuda et al, 2008), the transactivation domain (TAD) of the tumor suppressor p53 (Di Lello et al, 2006;Okuda and Nishimura, 2014). Although various partners of the p62 PH domain have been identified (Di Lello et al, 2005;Iyer et al, 1996;Mas et al, 2011), only two tertiary structures of the human p62 PH domain bound to the TFIIEa acidic domain (Okuda et al, 2008) and phosphorylated p53 TAD (Okuda and Nishimura, 2014) have been reported.…”

Section: Introductionmentioning

confidence: 99%

Structural Insight into the Mechanism of TFIIH Recognition by the Acidic String of the Nucleotide Excision Repair Factor XPC

et al. 2015

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In global genome repair (GGR), XPC detects damaged nucleotides and recruits TFIIH complex. The small acidic region of XPC binds to the pleckstrin homology (PH) domain of TFIIH subunit p62; however, the recognition mechanism remains elusive. Here, we use nuclear magnetic resonance to present the tertiary structure of XPC bound to the PH domain. The XPC acidic region forms a long string stabilized by insertion of Trp133 and Val136 into two separate hollows of the PH domain, coupled with extensive electrostatic contacts. Analysis of several XPC mutants revealed that particularly Trp133 is essential for binding to the PH domain. In cell lines stably expressing mutant XPC, alanine substitution at Trp133 or Trp133/Val136 compromised UV resistance, recruitment of TFIIH to DNA damage, and removal of UV-induced photoproducts from genomic DNA. These findings show how TFIIH complex is recruited by XPC to damaged DNA, advancing our understanding of the early stage of GGR.

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“…Lee et al demonstrated that the transactivation domain 2 of p53 protein forms a complex with CREB binding protein, and that a salt bridge between D49 of p53 protein and R2105 of nuclear coactivator binding domain of CREB binding protein may contribute to the binding specificity (11). Okuda and Nishimura suggested that the transactivation domain 2 of p53 protein binds the human TFIIH subunit p62 in an extended string-like conformation; they claimed that two phosphorylation sites, S46 and T55, play an important role (14) . It is worth noting that D49 locates between these amino acids.…”

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confidence: 99%

Prevalence of low-penetrant germline TP53 D49H mutation in Japanese cancer patients

et al. 2016

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Using whole exome sequencing data obtained from 1,685 Japanese cancer patients, we examined genetic variations of germline TP53 and found 10 types of non-synonymous single nucleotide variants. In the present study, we focused on 6 patients with germline D49H mutation located in the transactivation domain 2 of p53 protein, since the mutation seemed to be prevalent in cancer patients and to be pathogenic. According to the initial survey for family history of the proband with the germline TP53 D49H mutation, one osteosarcoma patient and his pedigree fulfill the criteria for Li-Fraumeni-like syndrome and the 2009 Chompret criteria for germline TP53 mutation screening. Since this patient possesses double germline mutations of TP53 D49H and A159D, further studies are required to evaluate contribution of the D49H mutation in this morbidity. The remaining 5 patients had family histories of cancer, but none fulfills the criteria either for the Li-Fraumeni/Li-Fraumeni-like syndromes or the 2009 Chompret criteria for germline TP53 mutation screening. It is possible to postulate that the germline TP53 D49H mutation is likely to be low-penetrant in some pedigrees. The present study also indicates that the survey for the germline TP53 mutation plays

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Extended String Binding Mode of the Phosphorylated Transactivation Domain of Tumor Suppressor p53

Cited by 49 publications

References 63 publications

Recognition of the disordered p53 transactivation domain by the transcriptional adapter zinc finger domains of CREB-binding protein

Recognition of the disordered p53 transactivation domain by the transcriptional adapter zinc finger domains of CREB-binding protein

Structural Insight into the Mechanism of TFIIH Recognition by the Acidic String of the Nucleotide Excision Repair Factor XPC

<b>Prevalence of low-penetrant germline </b><i><b>TP53</b></i><b> D49H mutation in Japanese cancer </b><b>patients </b>

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