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Recognition of the Disordered P53 Transactivation Domain by The Recognition of the disordered p53 transactivation PNAS PLUS domain by the transcriptional adapter zinc finger domains of CREB-binding protein Alexander S. Kroisa,b, Josephine C. Ferreona,b,1, Maria A. Martinez-Yamouta,b, H. Jane Dysona, and Peter E. Wrighta,b,2 aDepartment of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037; and bSkaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037 Contributed by Peter E. Wright, February 12, 2016 (sent for review January 8, 2016; reviewed by Mitsuhiko Ikura and Ishwar Radhakrishnan) An important component of the activity of p53 as a tumor suppres- bromodomain binds to the C-terminal regulatory domain after sor is its interaction with the transcriptional coactivators cyclic-AMP acetylation at K382 by the CBP HAT domain in response to response element-binding protein (CREB)-binding protein (CBP) and DNA damage (26). The unphosphorylated p53TAD binds to the p300, which activate transcription of p53-regulated stress response CBP/p300 domains with a broad range of affinities, with the genes and stabilize p53 against ubiquitin-mediated degradation. The strongest binding to TAZ2 (0.026 μM) (24, 25). It has been highest affinity interactions are between the intrinsically disordered hypothesized that each of the four TADs of the p53 tetramer N-terminal transactivation domain (TAD) of p53 and the TAZ1 and may bind to a separate domain of a single CBP/p300 molecule, TAZ2 domains of CBP/p300. The NMR spectra of simple binary resulting in an avidity effect that further stabilizes the p53– complexes of the TAZ1 and TAZ2 domains with the p53TAD suffer CBP/p300 complex and enhances p53-mediated transcription from exchange broadening, but innovations in construct design and (24, 25). The p53TAD, which is disordered throughout its isotopic labeling have enabled us to obtain high-resolution struc- length in the absence of binding partners (27, 28), is bipartite tures using fusion proteins, uniformly labeled in the case of the and contains two activation subdomains, between residues 1–39 TAZ2–p53TAD fusion and segmentally labeled through transintein and 40–61, which function both synergistically and differen- – splicing for the TAZ1 p53TAD fusion. The p53TAD is bipartite, with tially in mediating p53 function (29–31). The activation sub- two interaction motifs, termed AD1 and AD2, which fold to form domains contain short amphipathic interaction motifs (32–34), short amphipathic helices upon binding to TAZ1 and TAZ2 whereas termed AD1 (residues 18–26) and AD2 (residues 44–54) (Fig. intervening regions of the p53TAD remain flexible. Both the AD1 1A), that have a weak propensity for transient helical secondary and AD2 motifs bind to hydrophobic surfaces of the TAZ domains, structure in the unbound state (32–34) and are frequently ob- with AD2 making more extensive hydrophobic contacts consistent served to fold into stable amphipathic helices upon binding to with its greater contribution to the binding affinity. Binding of their partners (35–39). AD1 and AD2 is synergistic, and structural studies performed with isolated motifs can be misleading. The present structures of the full- BIOPHYSICS AND length p53TAD complexes demonstrate the versatility of the inter- Significance COMPUTATIONAL BIOLOGY actions available to an intrinsically disordered domain containing bipartite interaction motifs and provide valuable insights into the The tumor suppressor p53 regulates the cellular response to structural basis of the affinity changes that occur upon stress- genomic damage by recruiting the transcriptional coactivator related posttranslational modification. cyclic-AMP response element-binding protein (CREB)-binding protein (CBP) and its paralog p300 to activate stress response intrinsically disordered protein | binding motif | genes. We report NMR structures of the complexes formed transcriptional coactivator | intein | segmental labeling between the full-length, intrinsically disordered N-terminal transactivation domain of p53 and the transcriptional adapter zinc finger domains (TAZ1 and TAZ2) of CBP. Exchange broad- he tumor suppressor p53 plays a central role in the cellular ening of NMR spectra of the complexes was ameliorated by response to stress, functioning as an important signaling hub T using fusion proteins and segmental isotope labeling. The for the cellular response to various degrees of genomic damage structures show how the p53 transactivation domain uses bi- and instability (1, 2). p53 is a multidomain protein that contains partite binding motifs to recognize diverse partners, reveal the an N-terminal transactivation domain (TAD), a proline rich re- critical interactions required for high affinity binding, and gion, a core DNA-binding domain, a tetramerization domain, and provide insights into the mechanism by which phosphorylation a C-terminal regulatory domain (Fig. 1A). In unstressed cells, p53 enhances the ability of p53 to recruit CBP and p300. binds to the E3 ubiquitin ligase mouse double minute protein 2 (MDM2), which mediates ubiquitination and degradation of p53 Author contributions: A.S.K., J.C.F., M.A.M.-Y., H.J.D., and P.E.W. designed research; A.S.K., (3–6). In response to stress, p53 can be phosphorylated at more than J.C.F., and M.A.M.-Y. performed research; A.S.K., J.C.F., M.A.M.-Y., H.J.D., and P.E.W. 20 sites, 9 of which are located within the TAD (7). These modi- analyzed data; and A.S.K., H.J.D., and P.E.W. wrote the paper. fications lower the affinity of the p53TAD for MDM2 and promote Reviewers: M.I., Ontario Cancer Institute–University of Toronto; and I.R., Northwestern binding to the transcriptional coactivator cyclic-AMP response el- University. ement-binding protein (CREB)-binding protein (CBP) and its The authors declare no conflict of interest. paralog p300 (8–13). Binding of p53 to CBP/p300 facilitates Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, acetylation of the C-terminal domain of p53 and further inhibits www.pdb.org [PDB ID codes 5HPD (TAZ2–p53TAD), 5HP0 (TAZ2–p53AD2), and 5HOU (p53TAD–TAZ1)]. The NMR chemical shifts have been deposited in the BioMagResBank, its degradation (14, 15). The interaction between p53 and CBP/ www.bmrb.wisc.edu [accession nos. 30004 (TAZ2–p53TAD), 30003 (TAZ2–p53AD2), and p300 is also required for p53-mediated transcription and stabi- 30002 (p53TAD–TAZ1)]. – – lization of the p53 DNA interaction (16 18). Four domains of 1Present address: Department of Pharmacology, Baylor College of Medicine, Houston, CBP/p300 are involved in the interaction with the p53TAD: the TX 77030. folded transcriptional adapter zinc finger (TAZ) 1, KIX, and TAZ2 2To whom correspondence should be addressed. Email: [email protected]. domains, and the molten-globular nuclear coactivator-binding This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. domain (NCBD) (Fig. 1B) (16–25). In addition, the CBP/p300 1073/pnas.1602487113/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1602487113 PNAS | Published online March 14, 2016 | E1853–E1862 Downloaded by guest on September 28, 2021 have determined solution structures of the full-length p53TAD bound to the TAZ1 and TAZ2 domains of CBP, as well as the structure of the isolated p53AD2 domain bound to TAZ2. Results Design of Protein Constructs. NMR structural studies of p53/CBP complexes are frequently hindered by conformational averaging and exchange broadening, making structural restraints difficult to obtain (25, 38, 53). Binding of the p53TAD to the TAZ1 (Kd 0.9 μM) and TAZ2 (Kd 0.026 μM) domains occurs in fast to intermediate exchange on the chemical shift timescale, resulting in weak or missing resonances as a result of exchange broadening (25). Additionally, the presence of secondary binding sites pre- vents the use of a large excess of one binding partner in an effort to drive the interaction into the slow-exchange regime (54). These difficulties have limited previous structural characteriza- tion of p53TAD:TAZ2 complexes to the isolated AD1 or AD2 subdomains, for which the resonances are less broadened be- cause they exchange on a faster timescale (25, 38, 39). To obtain insights into the molecular basis for recognition of TAZ1 and TAZ2 by the bipartite p53TAD, we attempted to determine NMR structures of p53(13–61) in a 1:1 complex with each of the TAZ domains. Because of exchange broadening and missing resonances, we were able to obtain only preliminary, low-resolution structures that revealed the location and N-to-C Fig. 1. Schematic diagrams showing the domain structure of (A) p53 and (B) orientation of the AD1 and AD2 helices but could not provide CBP. (C) Construct design for the TAZ2–p53TAD fusion protein. (D)Intein atomic details of the interactions with TAZ1 and TAZ2. To – ligation scheme and final construct for the p53TAD TAZ1 fusion protein. circumvent this problem, we created fusion proteins, in which the Blue colors denote the p53TAD, with the AD1 and AD2 consensus regions outlined in blue in A. Interaction and catalytic domains identified in CBP are two interacting partners are joined by a flexible linker. Fusion shown in green for the nuclear receptor interaction domain (NRID), the KIX proteins enforce close proximity of the components of the com- domain, the bromodomain (bromo), the Cys-His rich domain-2 (CH2), the plex, increasing the effective concentration and association rate histone acetyl transferase domain (HAT), the ZZ domain, and the nuclear and driving the binding process into the slow-exchange regime, coactivator binding domain (NCBD) and in red for TAZ1 and in yellow for thereby reducing line broadening and enhancing spectral quality TAZ2. Intein and other tag and linker sequences are shown in gray. (55, 56). On the basis of the preliminary structure of the non- tethered complex, we designed a fusion protein containing the TAZ2 domain of mouse CBP (residues 1764–1855) joined to the The transcriptional adapter zinc finger (TAZ) (40) domains of p53TAD (residues 2–61) by a six-residue Gly-Ser repeat sequence CBP and p300 frequently act as scaffolds for the binding-related (Fig.
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