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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.
J Biol Chem. 2018 06 29; 293(26):9958-9969.JB

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.

Authors+Show Affiliations

From the Division of Immune Regulation, La Jolla Institute for Allergy and Immunology (LJI), La Jolla, California 92037.the Stanford Synchrotron Radiation Light Source, SLAC, Menlo Park, California 94025.From the Division of Immune Regulation, La Jolla Institute for Allergy and Immunology (LJI), La Jolla, California 92037. the Department of Medicine, University of California San Diego, La Jolla, California 92037, and.From the Division of Immune Regulation, La Jolla Institute for Allergy and Immunology (LJI), La Jolla, California 92037, dzajonc@lji.org. the Department of Internal Medicine, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

29720398

Citation

Bitra, Aruna, et al. "Crystal Structures of the Human 4-1BB Receptor Bound to Its Ligand 4-1BBL Reveal Covalent Receptor Dimerization as a Potential Signaling Amplifier." The Journal of Biological Chemistry, vol. 293, no. 26, 2018, pp. 9958-9969.
Bitra A, Doukov T, Croft M, et al. Crystal structures of the human 4-1BB receptor bound to its ligand 4-1BBL reveal covalent receptor dimerization as a potential signaling amplifier. J Biol Chem. 2018;293(26):9958-9969.
Bitra, A., Doukov, T., Croft, M., & Zajonc, D. M. (2018). Crystal structures of the human 4-1BB receptor bound to its ligand 4-1BBL reveal covalent receptor dimerization as a potential signaling amplifier. The Journal of Biological Chemistry, 293(26), 9958-9969. https://doi.org/10.1074/jbc.RA118.003176
Bitra A, et al. Crystal Structures of the Human 4-1BB Receptor Bound to Its Ligand 4-1BBL Reveal Covalent Receptor Dimerization as a Potential Signaling Amplifier. J Biol Chem. 2018 06 29;293(26):9958-9969. PubMed PMID: 29720398.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Crystal structures of the human 4-1BB receptor bound to its ligand 4-1BBL reveal covalent receptor dimerization as a potential signaling amplifier. AU - Bitra,Aruna, AU - Doukov,Tzanko, AU - Croft,Michael, AU - Zajonc,Dirk M, Y1 - 2018/05/02/ PY - 2018/03/27/received PY - 2018/04/25/revised PY - 2018/5/4/pubmed PY - 2019/1/18/medline PY - 2018/5/4/entrez KW - X-ray crystallography KW - cell surface receptor KW - protein structure KW - protein-protein interaction KW - recombinant protein expression KW - tumor necrosis factor (TNF) SP - 9958 EP - 9969 JF - The Journal of biological chemistry JO - J Biol Chem VL - 293 IS - 26 N2 - 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. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/29720398/Crystal_structures_of_the_human_4_1BB_receptor_bound_to_its_ligand_4_1BBL_reveal_covalent_receptor_dimerization_as_a_potential_signaling_amplifier_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)33839-4 DB - PRIME DP - Unbound Medicine ER -