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Rational Molecular Profiling of Receptor-Associated Late Transducer Peptide Selectivity Across Her/Rtk Kinases

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Abstract

Human epidermal growth factor receptor (Her) family signaling has been linked to diverse cancers, which includes four members: Her1, Her2, Her3 and Her4 as well as a variety of homologous analogs; they share a similar kinase domain fold but exhibit different functions in the cell. Receptor-associated late transducer (RALT) is a natural feedback regulator of Her signaling. The protein binds at and disrupts the activation interface of Her kinase domains to inactivate the kinases. Considering that the kinase domains and active sites of all Her members are highly conserved, RALT would have a broad specificity and cross-reactivity over different Her kinases. Here, we created a systematic selectivity profile of seven RALT peptides against four Her kinases and thirteen other receptor tyrosine kinases (Rtks) by combining homology modeling, ligand grafting, affinity scoring and binding assay, aiming to give a molecular insight into the recognition specificity and promiscuity of RALT peptides across these Her/Rtk kinases. The created profile was analyzed at structural and energetic levels; most peptides have only a low or moderate selectivity that cannot effectively differentiate different kinases with a high recognition specificity, thus rendering a potential off-target effect. The off-target, on the one hand, may cause RALT-derived peptidic inhibitors with significant adverse reactions and, on the other hand, make these inhibitors as promising candidates for the new use of old drugs. To practice the latter, two RALT peptides Sgm1-p2 and Sgm2-p2 with high theoretical selectivity for a case Rtk kinase were identified in the profile, which were compared with cognate small-molecule inhibitors. Structural analysis revealed that Sgm1-p2 and Sgm2-p2 bind to the kinase in a spatially independent but functionally dependent manner.

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References

  • Appert-Collin A, Hubert P, Crémel G, Bennasroune A (2015) Role of ErbB receptors in cancer cell migration and invasion. Front Pharmacol 6:283

    Article  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

    Article  CAS  Google Scholar 

  • Bhattacharya D, Nowotny J, Cao R, Cheng J (2016) 3Drefine: an interactive web server for efficient protein structure refinement. Nucleic Acids Res 44:W406–W409

    Article  CAS  Google Scholar 

  • Bordoli L, Kiefer F, Arnold K, Benkert P, Battey J, Schwede T (2009) Protein structure homology modeling using SWISS-MODEL workspace. Nat Protoc 4:1–13

    Article  CAS  Google Scholar 

  • Bose R, Zhang X (2009) The ErbB kinase domain: structural perspectives into kinase activation and inhibition. Exp Cell Res 315:649–658

    Article  CAS  Google Scholar 

  • Du Z, Lovly CM (2018) Mechanisms of receptor tyrosine kinase activation in cancer. Mol Cancer 17:58

    Article  Google Scholar 

  • Ferby I, Reschke M, Kudlacek O (2006) Mig6 is a negative regulator of EGF receptor-mediated skin morphogenesis and tumor formation. Nat Med 12:568–573

    Article  CAS  Google Scholar 

  • Fiorentino L, Pertica C, Fiorini M, Talora C, Crescenzi M, Castellani L, Alemà S, Benedetti P, Segatto O (2000) Inhibition of HER2 mitogenic and transforming activity by RALT, a mitogen-induced signal transducer which binds to the ErbB-2 kinase domain. Mol Cell Biol 20:7735–7750

    Article  CAS  Google Scholar 

  • García-Echeverría C, Pearson MA, Marti A, Meyer T (2004) In vivo antitumor activity of NVP-AEW541-A novel, potent, and selective inhibitor of the IGF-IR kinase. Cancer Cell 5:231–239

    Article  Google Scholar 

  • Han KQ, Wu G, Lv F (2013) Development of QSAR-improved statistical potential for the structure-based analysis of protein-peptide binding affinities. Mol Inform 32:783–792

    Article  CAS  Google Scholar 

  • Krieger E, Nabuurs SB, Vriend G (2003) Homology modeling. Methods Biochem Anal 44:509–523

    CAS  PubMed  Google Scholar 

  • Li N, Wei M (2017) Conversion of MIG6 peptide from the nonbinder to binder of lung cancer-related EGFR by phosphorylation and cyclization. Artif Cells Nanomed Biotechnol 45:1023–1028

    Article  CAS  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

    Article  CAS  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

    Article  CAS  Google Scholar 

  • Maity TK, Venugopalan A, Linnoila I (2015) Loss of MIG6 accelerates initiation and progression of mutant epidermal growth factor receptor-driven lung adenocarcinoma. Cancer Discov 5:534–549

    Article  CAS  Google Scholar 

  • Makki N, Thiel KW, Miller FJ (2013) The epidermal growth factor receptor and its ligands in cardiovascular disease. Int J Mol Sci 14:20597–20613

    Article  Google Scholar 

  • Park E, Kim N, Ficarro SB, Zhang Y, Lee BI, Cho A, Kim K, Park AKJ, Park WY, Murray B, Meyerson M, Beroukhim R, Marto JA, Cho J, Eck MJ (2015) Structure and mechanism of activity-based inhibition of the EGF receptor by RALT. Nat Struct Mol Biol 22:703–711

    Article  CAS  Google Scholar 

  • Schlessinger J (2000) Cell signaling by receptor tyrosine kinases. Cell 103:211–225

    Article  CAS  Google Scholar 

  • Schlessinger J (2002) Ligand-induced, receptor-mediated dimerization and activation of EGF receptor. Cell 110:669–672

    Article  CAS  Google Scholar 

  • Schlessinger J (2014) Receptor tyrosine kinases: legacy of the first two decades. Cold Spring Harb Perspect Biol 6:a008912

    Article  Google Scholar 

  • Segaert S, van Cutsem E (2005) Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol 16:1425–1433

    Article  CAS  Google Scholar 

  • Ségaliny AI, Tellez-Gabriel M, Heymann MF, Heymann D (2015) Receptor tyrosine kinases: characterisation, mechanism of action and therapeutic interests for bone cancers. J Bone Oncol 4:1–12

    Article  Google Scholar 

  • Singh D, Attri BK, Gill RK, Bariwal J (2016) Review on EGFR inhibitors: critical updates. Mini Rev Med Chem 16:1134–1166

    Article  CAS  Google Scholar 

  • Sirica AE (2008) Role of ErbB family receptor tyrosine kinases in intrahepatic cholangiocarcinoma. World J Gastroenterol 14:7033–7058

    Article  CAS  Google Scholar 

  • Spiga O, Bernini A, Scarselli M, Ciutti A, Bracci L, Lozzi L, Lelli B, Di Maro D, Calamandrei D, Niccolai N (2002) Peptide-protein interactions studied by surface plasmon and nuclear magnetic resonances. FEBS Lett 511:33–35

    Article  CAS  Google Scholar 

  • Takeda H, Goshima N, Nomura N (2010) High-throughput kinase assay based on surface plasmon resonance. Methods Mol Biol 627:131–145

    Article  CAS  Google Scholar 

  • Uniprot C (2017) UniProt: the universal protein knowledgebase. Nucleic Acids Res 45:D158–D169

    Article  Google Scholar 

  • Wagner JP, Wolf-Yadlin A, Sevecka M, Grenier JK, Root DE, Lauffenburger DA, MacBeath G (2013) Receptor tyrosine kinases fall into distinct classes based on their inferred signaling networks. Sci Signal 6:ra58

    Article  Google Scholar 

  • Wendt MK, Williams WK, Pascuzzi PE (2015) The antitumorigenic function of EGFR in metastatic breast cancer is regulated by expression of Mig6. Neoplasia 17:124–133

    Article  CAS  Google Scholar 

  • Yu CD, Guo AF, Zheng GH, Yang XW, Shi PC (2016) Design and optimization of peptide ligands to target breast cancer-positive HER2 by grafting and truncation of MIG6 peptide. Int J Pept Res Ther 22:229–236

    Article  CAS  Google Scholar 

  • Zhang X, Pickin A, Bose R (2007) Inhibition of the EGF receptor by binding of MIG6 to an activating kinase domain interface. Nature 450:741–744

    Article  CAS  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

    Article  CAS  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

    Article  CAS  Google Scholar 

  • Zhou P, Liu Q, Wu T, Miao Q, Shang S, Wang H, Chen Z, Wang S, Wang H (2021) Systematic comparison and comprehensive evaluation of 80 amino acid descriptors in peptide QSAR modeling. J Chem Inf Model 61:1718–1731

    Article  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the zch organization.

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Authors and Affiliations

  1. Department of Blood Transfusion, Zibo Central Hospital, Affiliated Hospital of Binzhou Medical University, Zibo, 255036, China

    Qi Zhang

  2. Department of Clinical Laboratory, Zibo Central Hospital, Affiliated Hospital of Binzhou Medical University, Zibo, 255036, China

    Tao Jing & Lina Zhao

  3. Department of Clinical Laboratory, Qingdao West Coast New District People’s Hospital, Qingdao, 266400, China

    Xiuxiang Cui

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  1. Qi Zhang
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  2. Tao Jing
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  3. Xiuxiang Cui
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  4. Lina Zhao
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Correspondence to Tao Jing.

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Zhang, Q., Jing, T., Cui, X. et al. Rational Molecular Profiling of Receptor-Associated Late Transducer Peptide Selectivity Across Her/Rtk Kinases. Int J Pept Res Ther 27, 1945–1951 (2021). https://doi.org/10.1007/s10989-021-10223-x

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  • DOI: https://doi.org/10.1007/s10989-021-10223-x

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