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Crystal structure of murine 4-1BB and its interaction with 4-1BBL support a role for galectin-9 in 4-1BB signaling.
J Biol Chem. 2018 01 26; 293(4):1317-1329.JB

Abstract

4-1BB (CD137) is a TNF receptor superfamily (TNFRSF) member that is thought to undergo receptor trimerization upon binding to its trimeric TNF superfamily ligand (4-1BBL) to stimulate immune responses. 4-1BB also can bind to the tandem repeat-type lectin galectin-9 (Gal-9), and signaling through mouse (m)4-1BB is reduced in galectin-9 (Gal-9)-deficient mice, suggesting a pivotal role of Gal-9 in m4-1BB activation. Here, using sulfur-SAD phasing, we determined the crystal structure of m4-1BB to 2.2-Å resolution. We found that similar to other TNFRSFs, m4-1BB has four cysteine-rich domains (CRDs). However, the organization of CRD1 and the orientation of CRD3 and CRD4 with respect to CRD2 in the m4-1BB structure distinctly differed from those of other TNFRSFs. Moreover, we mapped two Asn residues within CRD4 that are N-linked glycosylated and mediate m4-1BB binding to Gal-9. Kinetics studies of m4-1BB disclosed a very tight nanomolar binding affinity to m4-1BBL with an unexpectedly strong avidity effect. Both N- and C-terminal domains of Gal-9 bound m4-1BB, but with lower affinity compared with m4-1BBL. Although the TNF homology domain (THD) of human (h)4-1BBL forms non-covalent trimers, we found that m4-1BBL formed a covalent dimer via 2 cysteines absent in h4-1BBL. As multimerization and clustering is a prerequisite for TNFR intracellular signaling, and as m4-1BBL can only recruit two m4-1BB monomers, we hypothesize that m4-1BBL and Gal-9 act together to aid aggregation of m4-1BB monomers to efficiently initiate m4-1BB 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, Menlo Park, California 94025.From the Division of Immune Regulation, La Jolla Institute for Allergy and Immunology (LJI), La Jolla, California 92037.From the Division of Immune Regulation, La Jolla Institute for Allergy and Immunology (LJI), La Jolla, California 92037.From the Division of Immune Regulation, La Jolla Institute for Allergy and Immunology (LJI), La Jolla, California 92037.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. 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

29242193

Citation

Bitra, Aruna, et al. "Crystal Structure of Murine 4-1BB and Its Interaction With 4-1BBL Support a Role for Galectin-9 in 4-1BB Signaling." The Journal of Biological Chemistry, vol. 293, no. 4, 2018, pp. 1317-1329.
Bitra A, Doukov T, Wang J, et al. Crystal structure of murine 4-1BB and its interaction with 4-1BBL support a role for galectin-9 in 4-1BB signaling. J Biol Chem. 2018;293(4):1317-1329.
Bitra, A., Doukov, T., Wang, J., Picarda, G., Benedict, C. A., Croft, M., & Zajonc, D. M. (2018). Crystal structure of murine 4-1BB and its interaction with 4-1BBL support a role for galectin-9 in 4-1BB signaling. The Journal of Biological Chemistry, 293(4), 1317-1329. https://doi.org/10.1074/jbc.M117.814905
Bitra A, et al. Crystal Structure of Murine 4-1BB and Its Interaction With 4-1BBL Support a Role for Galectin-9 in 4-1BB Signaling. J Biol Chem. 2018 01 26;293(4):1317-1329. PubMed PMID: 29242193.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Crystal structure of murine 4-1BB and its interaction with 4-1BBL support a role for galectin-9 in 4-1BB signaling. AU - Bitra,Aruna, AU - Doukov,Tzanko, AU - Wang,Jing, AU - Picarda,Gaelle, AU - Benedict,Chris A, AU - Croft,Michael, AU - Zajonc,Dirk M, Y1 - 2017/12/14/ PY - 2017/08/29/received PY - 2017/12/01/revised PY - 2017/12/16/pubmed PY - 2018/11/28/medline PY - 2017/12/16/entrez KW - N-linked glycosylation KW - X-ray crystallography KW - cell surface receptor KW - galectin KW - protein structure KW - protein-protein interaction KW - recombinant protein expression KW - site-directed mutagenesis KW - surface plasmon resonance (SPR) KW - tumor necrosis factor (TNF) SP - 1317 EP - 1329 JF - The Journal of biological chemistry JO - J Biol Chem VL - 293 IS - 4 N2 - 4-1BB (CD137) is a TNF receptor superfamily (TNFRSF) member that is thought to undergo receptor trimerization upon binding to its trimeric TNF superfamily ligand (4-1BBL) to stimulate immune responses. 4-1BB also can bind to the tandem repeat-type lectin galectin-9 (Gal-9), and signaling through mouse (m)4-1BB is reduced in galectin-9 (Gal-9)-deficient mice, suggesting a pivotal role of Gal-9 in m4-1BB activation. Here, using sulfur-SAD phasing, we determined the crystal structure of m4-1BB to 2.2-Å resolution. We found that similar to other TNFRSFs, m4-1BB has four cysteine-rich domains (CRDs). However, the organization of CRD1 and the orientation of CRD3 and CRD4 with respect to CRD2 in the m4-1BB structure distinctly differed from those of other TNFRSFs. Moreover, we mapped two Asn residues within CRD4 that are N-linked glycosylated and mediate m4-1BB binding to Gal-9. Kinetics studies of m4-1BB disclosed a very tight nanomolar binding affinity to m4-1BBL with an unexpectedly strong avidity effect. Both N- and C-terminal domains of Gal-9 bound m4-1BB, but with lower affinity compared with m4-1BBL. Although the TNF homology domain (THD) of human (h)4-1BBL forms non-covalent trimers, we found that m4-1BBL formed a covalent dimer via 2 cysteines absent in h4-1BBL. As multimerization and clustering is a prerequisite for TNFR intracellular signaling, and as m4-1BBL can only recruit two m4-1BB monomers, we hypothesize that m4-1BBL and Gal-9 act together to aid aggregation of m4-1BB monomers to efficiently initiate m4-1BB signaling. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/29242193/Crystal_structure_of_murine_4_1BB_and_its_interaction_with_4_1BBL_support_a_role_for_galectin_9_in_4_1BB_signaling_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)39133-X DB - PRIME DP - Unbound Medicine ER -