2zjc Citations

Structure-function relationship of tumor necrosis factor (TNF) and its receptor interaction based on 3D structural analysis of a fully active TNFR1-selective TNF mutant.

Abstract

Tumor necrosis factor (TNF) is an important cytokine that suppresses carcinogenesis and excludes infectious pathogens to maintain homeostasis. TNF activates its two receptors [TNF receptor (TNFR) 1 and TNFR2], but the contribution of each receptor to various host defense functions and immunologic surveillance is not yet clear. Here, we used phage display techniques to generate receptor-selective TNF mutants that activate only one TNFR. These TNF mutants will be useful in the functional analysis of TNFR. Six amino acids in the receptor binding interface (near TNF residues 30, 80, and 140) were randomly mutated by polymerase chain reaction. Two phage libraries comprising over 5 million TNF mutants were constructed. By selecting the mutants without affinity for TNFR1 or TNFR2, we successfully isolated 4 TNFR2-selective candidates and 16 TNFR1-selective candidates, respectively. The TNFR1-selective candidates were highly mutated near residue 30, whereas TNFR2-selective candidates were highly mutated near residue 140, although both had conserved sequences near residues 140 and 30, respectively. This finding suggested that the phage display technique was suitable for identifying important regions for the TNF interaction with TNFR1 and TNFR2. Purified clone R1-6, a TNFR1-selective candidate, remained fully bioactive and had full affinity for TNFR1 without activating TNFR2, indicating the usefulness of the R1-6 TNF mutant in analyzing TNFR1 receptor function. To further elucidate the receptor selectivity of R1-6, we examined the structure of R1-6 by X-ray crystallography. The results suggested that R31A and R32G mutations strongly influenced electrostatic interaction with TNFR2, and that L29K mutation contributed to the binding of R1-6 to TNFR1. This phage display technique can be used to efficiently construct functional mutants for analysis of the TNF structure-function relationship, which might facilitate in silico drug design based on receptor selectivity.

Reviews citing this publication (14)

  1. TNF receptor 2 pathway: drug target for autoimmune diseases. Faustman D, Davis M. Nat Rev Drug Discov 9 482-493 (2010)
  2. Cytokines and epilepsy. Li G, Bauer S, Nowak M, Norwood B, Tackenberg B, Rosenow F, Knake S, Oertel WH, Hamer HM. Seizure 20 249-256 (2011)
  3. Engineering signal transduction pathways. Kiel C, Yus E, Serrano L. Cell 140 33-47 (2010)
  4. Regulation of TNF-α with a focus on rheumatoid arthritis. Moelants EA, Mortier A, Van Damme J, Proost P. Immunol. Cell Biol. 91 393-401 (2013)
  5. Tumor necrosis factor-alpha as a potential therapeutic target in idiopathic inflammatory myopathies. Stübgen JP. J. Neurol. 258 961-970 (2011)
  6. [Creation of TNFR1-selective antagonist and its therapeutic effects]. Nomura T, Abe Y, Yoshioka Y, Nakagawa S, Tsunoda S, Tsutsumi Y. Yakugaku Zasshi 130 63-68 (2010)
  7. Development of novel drug delivery systems using phage display technology for clinical application of protein drugs. Nagano K, Tsutsumi Y. Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. 92 156-166 (2016)
  8. Development of novel drug delivery systems using phage display technology for clinical application of protein drugs. Nagano K, Tsutsumi Y. Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. 92 156-166 (2016)
  9. Regulation of TNF-α with a focus on rheumatoid arthritis. Moelants EA, Mortier A, Van Damme J, Proost P. Immunol. Cell Biol. 91 393-401 (2013)
  10. Cytokines and epilepsy. Li G, Bauer S, Nowak M, Norwood B, Tackenberg B, Rosenow F, Knake S, Oertel WH, Hamer HM. Seizure 20 249-256 (2011)
  11. Tumor necrosis factor-alpha as a potential therapeutic target in idiopathic inflammatory myopathies. Stübgen JP. J. Neurol. 258 961-970 (2011)
  12. [Creation of TNFR1-selective antagonist and its therapeutic effects]. Nomura T, Abe Y, Yoshioka Y, Nakagawa S, Tsunoda S, Tsutsumi Y. Yakugaku Zasshi 130 63-68 (2010)
  13. Engineering signal transduction pathways. Kiel C, Yus E, Serrano L. Cell 140 33-47 (2010)
  14. TNF receptor 2 pathway: drug target for autoimmune diseases. Faustman D, Davis M. Nat Rev Drug Discov 9 482-493 (2010)

Articles citing this publication (16)

  1. Elucidating glycosaminoglycan-protein-protein interactions using carbohydrate microarray and computational approaches. Rogers CJ, Clark PM, Tully SE, Abrol R, Garcia KC, Goddard WA, Hsieh-Wilson LC. Proc. Natl. Acad. Sci. U.S.A. 108 9747-9752 (2011)
  2. Comparison of the inhibition mechanisms of adalimumab and infliximab in treating tumor necrosis factor α-associated diseases from a molecular view. Hu S, Liang S, Guo H, Zhang D, Li H, Wang X, Yang W, Qian W, Hou S, Wang H, Guo Y, Lou Z. J. Biol. Chem. 288 27059-27067 (2013)
  3. Enriching the human apoptosis pathway by predicting the structures of protein-protein complexes. Acuner Ozbabacan SE, Keskin O, Nussinov R, Gursoy A. J. Struct. Biol. 179 338-346 (2012)
  4. Structural basis for treating tumor necrosis factor α (TNFα)-associated diseases with the therapeutic antibody infliximab. Liang S, Dai J, Hou S, Su L, Zhang D, Guo H, Hu S, Wang H, Rao Z, Guo Y, Lou Z. J. Biol. Chem. 288 13799-13807 (2013)
  5. Crystal structure of TNFalpha complexed with a poxvirus MHC-related TNF binding protein. Yang Z, West AP, Bjorkman PJ. Nat. Struct. Mol. Biol. 16 1189-1191 (2009)
  6. Unraveling the binding mechanism of trivalent tumor necrosis factor ligands and their receptors. Reis CR, van Assen AH, Quax WJ, Cool RH. Mol. Cell Proteomics 10 M110.002808 (2011)
  7. Citrullination of TNF-α by peptidylarginine deiminases reduces its capacity to stimulate the production of inflammatory chemokines. Moelants EA, Mortier A, Grauwen K, Ronsse I, Van Damme J, Proost P. Cytokine 61 161-167 (2013)
  8. Fast binding kinetics and conserved 3D structure underlie the antagonistic activity of mutant TNF: useful information for designing artificial proteo-antagonists. Mukai Y, Nakamura T, Yoshioka Y, Shibata H, Abe Y, Nomura T, Taniai M, Ohta T, Nakagawa S, Tsunoda S, Kamada H, Yamagata Y, Tsutsumi Y. J. Biochem. 146 167-172 (2009)
  9. Crystallization and preliminary X-ray analysis of the tumour necrosis factor alpha-tumour necrosis factor receptor type 2 complex. Mukai Y, Nakamura T, Yoshioka Y, Tsunoda S, Kamada H, Nakagawa S, Yamagata Y, Tsutsumi Y. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 65 295-298 (2009)
  10. Correlating RANK ligand/RANK binding kinetics with osteoclast formation and function. Warren JT, Zou W, Decker CE, Rohatgi N, Nelson CA, Fremont DH, Teitelbaum SL. J. Cell. Biochem. 116 2476-2483 (2015)
  11. Novel mutants of human tumor necrosis factor with dominant-negative properties. Shingarova LN, Boldyreva EF, Yakimov SA, Guryanova SV, Dolgikh DA, Nedospasov SA, Kirpichnikov MP. Biochemistry Mosc. 75 1458-1463 (2010)
  12. [Production and properties of human tumor necrosis factor peptide fragments] Shingarova LN, Petrovskaia LE, Nekrasov AN, Kriukova EA, Boldyreva EF, Iakimov SA, Gur'ianova SV, Dolgikh DA, Kirpichnikov MP. Bioorg. Khim. 36 327-336 (2010)
  13. A novel recombinant slow-release TNF α-derived peptide effectively inhibits tumor growth and angiogensis. Ma Y, Zhao S, Shen S, Fang S, Ye Z, Shi Z, Hong A. Sci Rep 5 13595 (2015)
  14. Apoptosis through Death Receptors in Temporal Lobe Epilepsy-Associated Hippocampal Sclerosis. Teocchi MA, D'Souza-Li L. Mediators Inflamm. 2016 8290562 (2016)
  15. Structural modeling of tumor necrosis factor: A protein of immunological importance. Roy U. Biotechnol. Appl. Biochem. (2016)
  16. Rational design of TNFα binding proteins based on the de novo designed protein DS119. Zhu C, Zhang C, Zhang T, Zhang X, Shen Q, Tang B, Liang H, Lai L. Protein Sci. 25 2066-2075 (2016)