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Crystal structures of the human 4-1BB receptor bound to its ligand 4-1BBL reveal covalent receptor dimerization as a potential signaling amplifier.

Bitra A, Doukov T, Croft M, Zajonc DM
J Biol Chem 293 9958-9969 (2018)
Related entries: 6cpr, 6d3n

Cited: 24 times
EuropePMC logo PMID: 29720398

Abstract

Human (h)4-1BB (TNFRSF9 or CD137) is an inducible tumor necrosis factor receptor (TNFR) superfamily member that interacts with its cognate ligand h4-1BBL to promote T lymphocyte activation and proliferation. h4-1BB is currently being targeted with agonists in cancer immunotherapy. Here, we determined the crystal structures of unbound h4-1BBL and both WT h4-1BB and a dimerization-deficient h4-1BB mutant (C121S) in complex with h4-1BBL at resolutions between 2.7 and 3.2 Å. We observed that the structural arrangement of 4-1BBL, both unbound and in the complex, represents the canonical bell shape as seen in other similar TNF proteins and differs from the previously reported three-bladed propeller structure of 4-1BBL. We also found that the binding site for the receptor is at the crevice formed between two protomers of h4-1BBL, but that h4-1BB interacts predominantly with only one ligand protomer. Moreover, h4-1BBL lacked the conserved tyrosine residue in the DE loop that forms canonical interactions between other TNFR family molecules and their ligands, suggesting h4-1BBL engages h4-1BB through a distinct mechanism. Of note, we discovered that h4-1BB forms a disulfide-linked dimer because of the presence of an additional cysteine residue found in its cysteine-rich domain 4 (CRD4). As a result, h4-1BB dimerization, in addition to trimerization via h4-1BBL binding, could result in cross-linking of individual ligand-receptor complexes to form a 2D network that stimulates strong h4-1BB signaling. This work provides critical insights into the structural and functional properties of both h4-1BB and h4-1BBL and reveals that covalent receptor dimerization amplifies h4-1BB signaling.

Articles - 6cu0 mentioned but not cited (3)

  1. Crystal structures of the human 4-1BB receptor bound to its ligand 4-1BBL reveal covalent receptor dimerization as a potential signaling amplifier. Bitra A, Doukov T, Croft M, Zajonc DM. J Biol Chem 293 9958-9969 (2018)
  2. DSP107 combines inhibition of CD47/SIRPα axis with activation of 4-1BB to trigger anticancer immunity. Cendrowicz E, Jacob L, Greenwald S, Tamir A, Pecker I, Tabakman R, Ghantous L, Tamir L, Kahn R, Avichzer J, Aronin A, Amsili S, Zorde-Khvalevsky E, Gozlan Y, Vlaming M, Huls G, van Meerten T, Dranitzki ME, Foley-Comer A, Pereg Y, Peled A, Chajut A, Bremer E. J Exp Clin Cancer Res 41 97 (2022)
  3. Application of a Dy3Co0.6Cu0.4Hx Addition for Controlling the Microstructure and Magnetic Properties of Sintered Nd-Fe-B Magnets. Skotnicova K, Prokofev PA, Kolchugina NB, Burkhanov GS, Lukin AA, Koshkid'ko YS, Cegan T, Drulis H, Romanova T, Dormidontov NA. Materials (Basel) 12 E4235 (2019)


Reviews citing this publication (7)

  1. A comparison of chimeric antigen receptors containing CD28 versus 4-1BB costimulatory domains. Cappell KM, Kochenderfer JN. Nat Rev Clin Oncol 18 715-727 (2021)
  2. Receptor Oligomerization and Its Relevance for Signaling by Receptors of the Tumor Necrosis Factor Receptor Superfamily. Kucka K, Wajant H. Front Cell Dev Biol 8 615141 (2020)
  3. 4-1BBL as a Mediator of Cross-Talk between Innate, Adaptive, and Regulatory Immunity against Cancer. Martinez-Perez AG, Perez-Trujillo JJ, Garza-Morales R, Loera-Arias MJ, Saucedo-Cardenas O, Garcia-Garcia A, Rodriguez-Rocha H, Montes-de-Oca-Luna R. Int J Mol Sci 22 6210 (2021)
  4. The Glycosylation of Immune Checkpoints and Their Applications in Oncology. Zheng L, Yang Q, Li F, Zhu M, Yang H, Tan T, Wu B, Liu M, Xu C, Yin J, Cao C. Pharmaceuticals (Basel) 15 1451 (2022)
  5. 4-1BB immunotherapy: advances and hurdles. Singh R, Kim YH, Lee SJ, Eom HS, Choi BK. Exp Mol Med (2024)
  6. Agonism of 4-1BB for immune therapy: a perspective on possibilities and complications. Salek-Ardakani S, Zajonc DM, Croft M. Front Immunol 14 1228486 (2023)
  7. Rehabilitation: Neurogenic Bone Loss after Spinal Cord Injury. Leone GE, Shields DC, Haque A, Banik NL. Biomedicines 11 2581 (2023)

Articles citing this publication (14)

  1. Tumor-targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy. Claus C, Ferrara C, Xu W, Sam J, Lang S, Uhlenbrock F, Albrecht R, Herter S, Schlenker R, Hüsser T, Diggelmann S, Challier J, Mössner E, Hosse RJ, Hofer T, Brünker P, Joseph C, Benz J, Ringler P, Stahlberg H, Lauer M, Perro M, Chen S, Küttel C, Bhavani Mohan PL, Nicolini V, Birk MC, Ongaro A, Prince C, Gianotti R, Dugan G, Whitlow CT, Solingapuram Sai KK, Caudell DL, Burgos-Rodriguez AG, Cline JM, Hettich M, Ceppi M, Giusti AM, Crameri F, Driessen W, Morcos PN, Freimoser-Grundschober A, Levitsky V, Amann M, Grau-Richards S, von Hirschheydt T, Tournaviti S, Mølhøj M, Fauti T, Heinzelmann-Schwarz V, Teichgräber V, Colombetti S, Bacac M, Zippelius A, Klein C, Umaña P. Sci Transl Med 11 eaav5989 (2019)
  2. 4-1BB costimulation promotes CAR T cell survival through noncanonical NF-κB signaling. Philipson BI, O'Connor RS, May MJ, June CH, Albelda SM, Milone MC. Sci Signal 13 eaay8248 (2020)
  3. Immunodeficiency and EBV-induced lymphoproliferation caused by 4-1BB deficiency. Alosaimi MF, Hoenig M, Jaber F, Platt CD, Jones J, Wallace J, Debatin KM, Schulz A, Jacobsen E, Möller P, Shamseldin HE, Abdulwahab F, Ibrahim N, Alardati H, Almuhizi F, Abosoudah IF, Basha TA, Chou J, Alkuraya FS, Geha RS. J Allergy Clin Immunol 144 574-583.e5 (2019)
  4. An anti-PD-1-GITR-L bispecific agonist induces GITR clustering-mediated T cell activation for cancer immunotherapy. Chan S, Belmar N, Ho S, Rogers B, Stickler M, Graham M, Lee E, Tran N, Zhang D, Gupta P, Sho M, MacDonough T, Woolley A, Kim H, Zhang H, Liu W, Zheng P, Dezso Z, Halliwill K, Ceccarelli M, Rhodes S, Thakur A, Forsyth CM, Xiong M, Tan SS, Iyer R, Lake M, Digiammarino E, Zhou L, Bigelow L, Longenecker K, Judge RA, Liu C, Trumble M, Remis JP, Fox M, Cairns B, Akamatsu Y, Hollenbaugh D, Harding F, Alvarez HM. Nat Cancer 3 337-354 (2022)
  5. Cancer immune therapy with PD-1-dependent CD137 co-stimulation provides localized tumour killing without systemic toxicity. Qiao Y, Qiu Y, Ding J, Luo N, Wang H, Ling X, Sun J, Wu Z, Wang Y, Liu Y, Guo F, Sun T, Shen W, Zhang M, Wu D, Chen B, Xu W, Wang X. Nat Commun 12 6360 (2021)
  6. Crystal structure of the m4-1BB/4-1BBL complex reveals an unusual dimeric ligand that undergoes structural changes upon 4-1BB receptor binding. Bitra A, Doukov T, Destito G, Croft M, Zajonc DM. J Biol Chem 294 1831-1845 (2019)
  7. An engineered 4-1BBL fusion protein with "activity on demand". Mock J, Stringhini M, Villa A, Weller M, Weiss T, Neri D. Proc Natl Acad Sci U S A 117 31780-31788 (2020)
  8. Structural delineation and phase-dependent activation of the costimulatory CD27:CD70 complex. Liu W, Maben Z, Wang C, Lindquist KC, Li M, Rayannavar V, Lopez Armenta I, Nager A, Pascua E, Dominik PK, Oyen D, Wang H, Roach RC, Allan CM, Mosyak L, Chaparro-Riggers J. J Biol Chem 297 101102 (2021)
  9. Targeting the 4-1BB costimulatory molecule through single chain antibodies promotes the human T-cell response. Bagheri S, Safaie Qamsari E, Yousefi M, Riazi-Rad F, Sharifzadeh Z. Cell Mol Biol Lett 25 28 (2020)
  10. N-Glycosylation Facilitates 4-1BB Membrane Localization by Avoiding Its Multimerization. Sun R, Kim AMJ, Murray AA, Lim SO. Cells 11 162 (2022)
  11. Agonistic CD27 antibody potency is determined by epitope-dependent receptor clustering augmented through Fc-engineering. Heckel F, Turaj AH, Fisher H, Chan HTC, Marshall MJE, Dadas O, Penfold CA, Inzhelevskaya T, Mockridge CI, Alvarado D, Tews I, Keler T, Beers SA, Cragg MS, Lim SH. Commun Biol 5 229 (2022)
  12. A PD-L1-targeting chimeric switch receptor enhances efficacy of CAR-T cell for pleural and peritoneal metastasis. Ma Q, He X, Zhang B, Guo F, Ou X, Yang Q, Shu P, Chen Y, Li K, Gao G, Zhu Y, Qin D, Tang J, Li X, Jing M, Zhao J, Mo Z, Liu N, Zeng Y, Zhou K, Feng M, Liao W, Lei W, Li Q, Li D, Wang Y. Signal Transduct Target Ther 7 380 (2022)
  13. A novel 4-1BB/HER2 bispecific antibody shows potent antitumor activities by increasing and activating tumor-infiltrating T cells. Shen A, Liu W, Wang H, Zeng X, Wang M, Zhang D, Zhao Q, Fang Q, Wang F, Cheng L, Shen G, Li Y. Am J Cancer Res 13 3246-3256 (2023)
  14. An Fc-muted bispecific antibody targeting PD-L1 and 4-1BB induces antitumor immune activity in colorectal cancer without systemic toxicity. Cheng LS, Zhu M, Gao Y, Liu WT, Yin W, Zhou P, Zhu Z, Niu L, Zeng X, Zhang D, Fang Q, Wang F, Zhao Q, Zhang Y, Shen G. Cell Mol Biol Lett 28 47 (2023)


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