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Crystal structure of the m4-1BB/4-1BBL complex reveals an unusual dimeric ligand that undergoes structural changes upon 4-1BB receptor binding.
J Biol Chem. 2019 02 08; 294(6):1831-1845.JB

Abstract

The interaction between the receptor 4-1BB and its ligand 4-1BBL provides co-stimulatory signals for T-cell activation and proliferation. However, differences in the mouse and human molecules might result in differential engagement of this pathway. Here, we report the crystal structure of mouse 4-1BBL and of the mouse 4-1BB/4-1BBL complex, which together provided insights into the molecular mechanism by which m4-1BBL and its cognate receptor recognize each other. Unlike all human or mouse tumor necrosis factor ligands that form noncovalent and mostly trimeric assemblies, the m4-1BBL structure formed a disulfide-linked dimeric assembly. The structure disclosed that certain differences in the amino acid composition along the intramolecular interface, together with two specific residues (Cys-246 and Ser-256) present exclusively in m4-1BBL, are responsible for this unique dimerization. Unexpectedly, upon m4-1BB binding, m4-1BBL undergoes structural changes within each protomer; moreover, the individual m4-1BBL protomers rotate relative to each other, yielding a dimerization interface with more inter-subunit interactions. We also observed that in the m4-1BB/4-1BBL complex, each receptor monomer binds exclusively to a single ligand subunit with contributions of cysteine-rich domain 1 (CRD1), CRD2, and CRD3. Furthermore, structure-guided mutagenesis of the binding interface revealed that novel binding interactions with the GH loop, rather than the DE loop, are energetically critical and define the m4-1BB receptor selectivity for m4-1BBL. A comparison with the human 4-1BB/4-1BBL complex highlighted several differences between the ligand- and receptor-binding interfaces, providing an explanation for the absence of inter-species cross-reactivity between human and mouse 4-1BB and 4-1BBL molecules.

Authors+Show Affiliations

From the Division of Immune Regulation, La Jolla Institute for Immunology (LJI), La Jolla, California 92037.the Stanford Synchrotron Radiation Lightsource, SLAC, Menlo Park, California 94025.Kirin Kyowa Hakko Pharmaceutical Research, La Jolla, California 92037.From the Division of Immune Regulation, La Jolla Institute for 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 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

30545939

Citation

Bitra, Aruna, et al. "Crystal Structure of the m4-1BB/4-1BBL Complex Reveals an Unusual Dimeric Ligand That Undergoes Structural Changes Upon 4-1BB Receptor Binding." The Journal of Biological Chemistry, vol. 294, no. 6, 2019, pp. 1831-1845.
Bitra A, Doukov T, Destito G, et al. Crystal structure of the m4-1BB/4-1BBL complex reveals an unusual dimeric ligand that undergoes structural changes upon 4-1BB receptor binding. J Biol Chem. 2019;294(6):1831-1845.
Bitra, A., Doukov, T., Destito, G., Croft, M., & Zajonc, D. M. (2019). Crystal structure of the m4-1BB/4-1BBL complex reveals an unusual dimeric ligand that undergoes structural changes upon 4-1BB receptor binding. The Journal of Biological Chemistry, 294(6), 1831-1845. https://doi.org/10.1074/jbc.RA118.006297
Bitra A, et al. Crystal Structure of the m4-1BB/4-1BBL Complex Reveals an Unusual Dimeric Ligand That Undergoes Structural Changes Upon 4-1BB Receptor Binding. J Biol Chem. 2019 02 8;294(6):1831-1845. PubMed PMID: 30545939.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Crystal structure of the m4-1BB/4-1BBL complex reveals an unusual dimeric ligand that undergoes structural changes upon 4-1BB receptor binding. AU - Bitra,Aruna, AU - Doukov,Tzanko, AU - Destito,Giuseppe, AU - Croft,Michael, AU - Zajonc,Dirk M, Y1 - 2018/12/13/ PY - 2018/10/17/received PY - 2018/11/28/revised PY - 2018/12/14/pubmed PY - 2019/6/27/medline PY - 2018/12/15/entrez KW - 4-1BB KW - 4-1BB ligand KW - CD137 KW - CD137L KW - TNFRSF9 KW - X-ray crystallography KW - cell surface receptor KW - immune cell KW - protein structure KW - protein–protein interaction KW - tumor necrosis factor (TNF) SP - 1831 EP - 1845 JF - The Journal of biological chemistry JO - J Biol Chem VL - 294 IS - 6 N2 - The interaction between the receptor 4-1BB and its ligand 4-1BBL provides co-stimulatory signals for T-cell activation and proliferation. However, differences in the mouse and human molecules might result in differential engagement of this pathway. Here, we report the crystal structure of mouse 4-1BBL and of the mouse 4-1BB/4-1BBL complex, which together provided insights into the molecular mechanism by which m4-1BBL and its cognate receptor recognize each other. Unlike all human or mouse tumor necrosis factor ligands that form noncovalent and mostly trimeric assemblies, the m4-1BBL structure formed a disulfide-linked dimeric assembly. The structure disclosed that certain differences in the amino acid composition along the intramolecular interface, together with two specific residues (Cys-246 and Ser-256) present exclusively in m4-1BBL, are responsible for this unique dimerization. Unexpectedly, upon m4-1BB binding, m4-1BBL undergoes structural changes within each protomer; moreover, the individual m4-1BBL protomers rotate relative to each other, yielding a dimerization interface with more inter-subunit interactions. We also observed that in the m4-1BB/4-1BBL complex, each receptor monomer binds exclusively to a single ligand subunit with contributions of cysteine-rich domain 1 (CRD1), CRD2, and CRD3. Furthermore, structure-guided mutagenesis of the binding interface revealed that novel binding interactions with the GH loop, rather than the DE loop, are energetically critical and define the m4-1BB receptor selectivity for m4-1BBL. A comparison with the human 4-1BB/4-1BBL complex highlighted several differences between the ligand- and receptor-binding interfaces, providing an explanation for the absence of inter-species cross-reactivity between human and mouse 4-1BB and 4-1BBL molecules. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/30545939/Crystal_structure_of_the_m4_1BB/4_1BBL_complex_reveals_an_unusual_dimeric_ligand_that_undergoes_structural_changes_upon_4_1BB_receptor_binding_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)36832-0 DB - PRIME DP - Unbound Medicine ER -