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Targeting Human Hippo TEAD Binding Interface with YAP/TAZ-Derived, Flexibility-Reduced Peptides in Gastric Cancer

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Abstract

Human Hippo signaling pathway plays an important role in the tumorigenesis of diverse cancers and has been recognized as an attractive therapeutic target of gastric cancer. The transcriptional coactivators Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) are the major downstream effectors of Hippo, which interact primarily with transcriptional enhanced associate domain (TEAD) protein through their TEAD-binding domain (TBD). Competitive disruption of the TEAD–YAP/TAZ interaction using peptide inhibitors has been exploited as a potential strategy to treat gastric cancer by regulating Hippo signaling. Here, the crystal structures of TEAD complex with YAP/TAZ TBD domain are investigated systematically at structural, energetic and dynamic levels, from which two binding hotspots are identified; they separately correspond to an α-helix and a Ω-loop of TBD domain, and contribute essentially to the complex interaction. Several linear peptide segments derived from the hotspot regions are highly flexibility and exhibit moderate or modest affinity for TEAD. The Ω-loop-derived peptides are found to have a higher affinity, which are cyclized by introducing a disulfide bridge across their two termini. Affinity assay confirms that the cyclization can considerably improve peptide affinity by 3.7–6.6-fold. Computational analysis reveals that the designed cyclic peptides exhibit a decreased flexibility and intrinsic disorder; they can roughly maintain in native active conformation out of TBD protein context, with a reduced entropy cost upon binding to TEAD.

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References

  • Arkin MR, Tang Y, Wells JA (2014) Small-molecule inhibitors of protein-protein interactions: progressing toward the reality. Chem Biol 21:1102–1114

    CAS  PubMed  PubMed Central  Google Scholar 

  • Anandakrishnan R, Aguilar B, Onufriev AV (2012) H++ 3.0: automating pK prediction and the preparation of biomolecular structures for atomistic molecular modeling and simulation. Nucleic Acids Res 4:W537–W541

    Google Scholar 

  • Bai Z, Hou S, Zhang S, Li Z, Zhou P (2017) Targeting self-binding peptides as a novel strategy to regulate protein activity and function: a case study on the proto-oncogene tyrosine protein kinase c-Src. J Chem Inf Model 57:835–845

    CAS  PubMed  Google Scholar 

  • Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The protein data bank. Nucleic Acids Res 28:235–242

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424

    PubMed  Google Scholar 

  • Chen K, Huang L, Shen B (2019) Rational cyclization-based minimization of entropy penalty upon the binding of Nrf2-derived linear peptides to Keap1: a new strategy to improve therapeutic peptide activity against sepsis. Biophys Chem 244:22–28

    CAS  PubMed  Google Scholar 

  • Crook ZR, Sevilla GP, Friend D, Brusniak MY, Bandaranayake AD, Clarke M, Gewe M, Mhyre AJ, Baker D, Strong RK, Bradley P, Olson JM (2017) Mammalian display screening of diverse cystine-dense peptides for difficult to drug targets. Nat Commun 8:2244

    PubMed  PubMed Central  Google Scholar 

  • Dombrowsky MJ, Jager S, Schiller B, Mayer BE, Stammler S, Hamacher K (2018) StreaMD: advanced analysis of molecular synamics using R. J Comput Chem 39:1666–1674

    CAS  PubMed  Google Scholar 

  • Darden T, York D, Pedersen L (1983) Particale mesh Ewald and N.log(N) method for Ewald sums in large systems. J Chem Phys 98:10089–10092

    Google Scholar 

  • Fosgerau K, Hoffmann T (2015) Peptide therapeutics: current status and future directions. Drug Discov Today 20:122–128

    CAS  PubMed  Google Scholar 

  • Furet P, Salem B, Mesrouze T, Schmelzle T, Lewis I, Kallen J, Chène P (2019) Structure-based design of potent linear peptide inhibitors of the YAP-TEAD protein-protein interaction derived from the YAP omega-loop sequence. Bioorg Med Chem Lett 29:2316–2319

    CAS  PubMed  Google Scholar 

  • Gromiha MM, Yugandhar K, Jemimah S (2017) Protein-protein interactions: scoring schemes and binding affinity. Curr Opin Struct Biol 44:31–38

    CAS  PubMed  Google Scholar 

  • Hau JC, Erdmann D, Mesrouze Y, Furet P, Fontana P, Zimmermann C, Schmelzle T, Hofmann F, Chène P (2013) The TEAD4-YAP/TAZ protein-protein interaction: expected similarities and unexpected differences. ChemBioChem 14:1218–1225

    CAS  PubMed  Google Scholar 

  • Holden JK, Cunningham CN (2018) Targeting the Hippo pathway and cancer through the TEAD family of transcription factors. Cancers 10:81

    PubMed Central  Google Scholar 

  • Homeyer N, Gohlke H (2012) Free energy calculations by the molecular mechanics Poisson-Boltzmann surface area method. Mol Inf 31:114–122

    CAS  Google Scholar 

  • Hou T, Zhang W, Case DA, Wang W (2008) Characterization of domain-peptide interaction interface: a case study on the amphiphysin-1 SH3 domain. J Mol Biol 376:1201–1214

    CAS  PubMed  Google Scholar 

  • Hu H, Yang S, Zheng J, Mao G (2017) Structure-based derivation of peptide inhibitors to target TGF-β1 receptor for the suppression of hypertrophic scarring fibroblast activation. Chem Biol Drug Des 90:345–351

    CAS  PubMed  Google Scholar 

  • Jiao S, Wang H, Shi Z, Dong A, Zhang W, Song X, He F, Wang Y, Zhang Z, Wang W, Wang X, Guo T, Li P, Zhao Y, Ji H, Zhang L, Zhou Z (2014) A peptide mimicking VGLL4 function acts as a Yes antagonist therapy against gastric cancer. Cancer Cell 25:166–180

    CAS  PubMed  Google Scholar 

  • Li Z, Miao Q, Yan F, Meng Y, Zhou P (2019a) Machine learning in quantitative protein-peptide affinity prediction: implications for therapeutic peptide design. Curr Drug Metab 20:170–176

    CAS  PubMed  Google Scholar 

  • Li Z, Yan F, Miao Q, Meng Y, Wen L, Jiang Q, Zhou P (2019b) Self-binding peptides: binding-upon-folding versus folding-upon-binding. J Theor Biol 469:25–34

    CAS  PubMed  Google Scholar 

  • London N, Raveh B, Movshovitz-Attias D, Schueler-Furman O (2010) Can self-inhibitory peptides be derived from the interfaces of globular protein-protein interactions? Proteins 78:3140–3149

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ma Y, Yang Y, Wang F, Wei Q, Qin H (2015) Hippo-YAP signaling pathway: a new paradigm for cancer therapy. Int J Cancer 137:2275–2286

    CAS  PubMed  Google Scholar 

  • Maier JA, Martinez C, Kasavajhala K, Wickstrom L, Hauser KE, Simmerling C (2015) ff14SB: improving the accuracy of protein side chain and backbone parameters from ff99SB. J Chem Theory Comput 11:3696–3713

    CAS  PubMed  PubMed Central  Google Scholar 

  • Moroishi T, Hansen CG, Guan KL (2015) The emerging roles of YAP and TAZ in cancer. Nat Rev Cancer 15:73–79

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ndagi U, Mhlongo NN, Soliman ME (2017) The impact of Thr91 mutation on c-Src resistance to UM-164: molecular dynamics study revealed a new opportunity for drug design. Mol Biosyst 13:1157–1171

    CAS  PubMed  Google Scholar 

  • Pobbati AV, Hong W (2020) A combat with the YAP/TAZ-TEAD oncoproteins for cancer therapy. Theranostics 10:3622–3635

    CAS  PubMed  PubMed Central  Google Scholar 

  • Qian H, He P, Lv F, Wu W (2019) Genome-wide analysis of LXXLL-mediated DAX1/SHP-nuclear receptor interaction network and rational design of stapled LXXLL-based peptides to target the specific network profile. Int J Biol Macromol 129:13–22

    CAS  PubMed  Google Scholar 

  • Rawla P, Barsouk A (2019) Epidemiology of gastric cancer: global trends, risk factors and prevention. Prz Gastroenterol 14:26–38

    CAS  PubMed  Google Scholar 

  • Ryckaert JP, Ciccotti G, Berendsen HJC (1997) Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J Comput Phys 23:327–341

    Google Scholar 

  • Santucci M, Vignudelli T, Ferrari S, Mor M, Scalvini L, Bolognesi ML, Uliassi E, Costi MP (2015) The Hippo pathway and YAP/TAZ-TEAD protein-protein interaction as targets for regenerative medicine and cancer treatment. J Med Chem 58:4857–4873

    CAS  PubMed  Google Scholar 

  • Song D, Wang W, Ye W, Ji D, Luo R, Chen HF (2017) ff14IDPs force field improving the conformation sampling of intrinsically disordered proteins. Chem Biol Drug Des 89:5–15

    CAS  PubMed  Google Scholar 

  • Tian F, Lv Y, Zhou P, Yang L (2011) Characterization of PDZ domain-peptide interactions using an integrated protocol of QM/MM, PB/SA, and CFEA analyses. J Comput Aided Mol Des 25:947–958

    CAS  PubMed  Google Scholar 

  • Wild CP, Weiderpass E, Stewart BW (2019) WHO world cancer report. IARC publications, WHO press

    Google Scholar 

  • Yang C, Zhang S, He P, Wang C, Huang J, Zhou P (2015a) Self-binding peptides: folding or binding. J Chem Inf Model 55:329–342

    CAS  PubMed  Google Scholar 

  • Yang C, Wang C, Zhang S, Huang J, Zhou P (2015b) Structural and energetic insights into the intermolecular interaction among human leukocyte antigens, clinical hypersensitive drugs and antigenic peptides. Mol Simul 41:741–751

    CAS  Google Scholar 

  • Yang C, Zhang S, Bai Z, Hou S, Wu D, Huang J, Zhou P (2016) A two-step binding mechanism for the self-binding peptide recognition of target domains. Mol Biosyst 12:1201–1213

    CAS  PubMed  Google Scholar 

  • Yang Y, Liu H, Yao X (2012) Understanding the molecular basis of MK2-p38α signaling complex assembly: insights into protein-protein interaction by molecular dynamics and free energy studies. Mol Biosyst 8:2106–2118

    CAS  PubMed  Google Scholar 

  • Yu H, Zhou P, Deng M, Shang Z (2014) Indirect readout in protein-peptide recognition: a different story from classical biomolecular recognition. J Chem Inf Model 54:2022–2032

    CAS  PubMed  Google Scholar 

  • Yuan S, Chan HCS, Hu Z (2017) Using PyMOL as a platform for computational drug design. WIREs Comput Mol Sci 7:e1298

    Google Scholar 

  • Zhang J, Pan Y, Liao D, Tang J, Yao D (2018a) Peptide 17, an inhibitor of YAP/TEAD4 pathway, mitigates lung cancer malignancy. Trop J Pharm Res 17:1255–1262

    CAS  Google Scholar 

  • Zhang W, Zhong B, Zhang C, Wang Y, Guo S, Luo C, Zhan Y (2018b) Structural modeling of osteoarthritis ADAMTS4 complex with its cognate inhibitory protein TIMP3 and rational derivation of cyclic peptide inhibitors from the complex interface to target ADAMTS4. Bioorg Chem 76:13–22

    CAS  PubMed  Google Scholar 

  • Zhang Y, Schulten K, Gruebele M, Bansal PS, Wilson D, Daly NL (2016) Disulfide bridges: bringing together frustrated structure in a bioactive peptide. Biophys J 110:1744–1752

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Z, Lin Z, Zhou Z, Shen HC, Yan SF, Mayweg AV, Xu Z, Qin N, Wong JC, Zhang Z, Rong Y, Fry DC, Hu T (2014) Structure-based design and synthesis of potent cyclic peptides inhibiting the YAP-TEAD protein-protein interaction. ACS Med Chem Lett 5:993–998

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang D, He D, Pan X, Liu L (2020) Rational design and intramolecular cyclization of hotspot peptide segments at YAP-TEAD4 complex interface. Protein Pept Lett 27:1–10

    Google Scholar 

  • Zhou Z, Hu T, Xu Z, Lin Z, Zhang Z, Feng T, Zhu L, Rong Y, Shen H, Luk JM, Zhang X, Qin N (2017) Targeting Hippo pathway by specific interruption of YAP-TEAD interaction using cyclic YAP-like peptides. FASEB J 31:1767

    Google Scholar 

  • Zhou P, Wang C, Tian F, Ren Y, Yang C, Huang J (2013a) Biomacromolecular quantitative structure-activity relationship (BioQSAR): a proof-of-concept study on the modeling, prediction and interpretation of protein-protein binding affinity. J Comput Aided Mol Des 27:67–78

    PubMed  Google Scholar 

  • Zhou P, Yang C, Ren Y, Wang C, Tian F (2013b) What are the ideal properties for functional food peptides with antihypertensive effect? A computational peptidology approach. Food Chem 141:2967–2973

    CAS  PubMed  Google Scholar 

  • Zhou P, Zhang S, Wang Y, Yang C, Huang J (2016) Structural modeling of HLA-B*1502 peptide carbamazepine T-cell receptor complex architecture: implication for the molecular mechanism of carbamazepine-induced Stevens-Johnson syndrome toxic epidermal necrolysis. J Biomol Struct Dyn 34:1806–1817

    CAS  PubMed  Google Scholar 

  • Zhou P, Hou S, Bai Z, Li Z, Wang H, Chen Z, Meng Y (2018) Disrupting the intramolecular interaction between proto-oncogene c-Src SH3 domain and its self-binding peptide PPII with rationally designed peptide ligands. Artif Cells Nanomed Biotechnol 46:1122–1131

    CAS  PubMed  Google Scholar 

  • Zhou P, Miao Q, Yan F, Li Z, Jiang Q, Wen L, Meng Y (2019) Is protein context responsible for peptide-mediated interactions? Mol Omics 15:280–295

    CAS  PubMed  Google Scholar 

  • Zhou P, Yan F, Miao Q, Chen Z, Wang H (2020) Why the first self-binding peptide of human c-Src kinase does not contain class II motif but can bind to its cognate Src homology 3 domain in class II mode? J Biomol Struct Dyn. https://doi.org/10.1080/07391102.2019.1709547

    Article  PubMed  Google Scholar 

  • Zygulska AL, Krzemieniecki K, Pierzchalski P (2017) Hippo pathway —brief overview of its relevance in cancer. J Physiol Pharmacol 68:311–335

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Scientific Research Foundation provided by Pudong Hospital affiliated to Fudan University (No. 201511) and the Talents Training Program of Pudong Hospital affiliated to Fudan University (No. px201504).

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Correspondence to Yingjun Quan or Zhijun Min.

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Wu, D., Luo, L., Yang, Z. et al. Targeting Human Hippo TEAD Binding Interface with YAP/TAZ-Derived, Flexibility-Reduced Peptides in Gastric Cancer. Int J Pept Res Ther 27, 119–128 (2021). https://doi.org/10.1007/s10989-020-10069-9

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