TRAIL-R2 Superoligomerization Induced by Human Monoclonal Agonistic Antibody KMTR2

The fully human monoclonal antibody KMTR2 acts as a strong direct agonist for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 2 (TRAIL-R2), which is capable of inducing apoptotic cell death without cross-linking. To investigate the mechanism of direct agonistic activity indu...

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Bibliographic Details
Published in:Scientific reports 2015-12, Vol.5 (1), p.17936-17936, Article 17936
Main Authors: Tamada, Taro, Shinmi, Daisuke, Ikeda, Masahiro, Yonezawa, Yasushi, Kataoka, Shiro, Kuroki, Ryota, Mori, Eiji, Motoki, Kazuhiro
Format: Article
Language:English
Subjects:
Animals
Antibodies, Monoclonal - chemistry
Antibodies, Monoclonal - genetics
Antibodies, Monoclonal - pharmacology
Apoptosis
Apoptosis - drug effects
Binding Sites - genetics
Cell death
Cell Line, Tumor
Cell Survival - drug effects
CHO Cells
Complementarity
Complementarity-determining region
Complementarity-determining region 2
Cricetinae
Cricetulus
Crystal structure
Crystallography, X-Ray
Fab
Humans
Immunoglobulin Fab Fragments - chemistry
Immunoglobulin Fab Fragments - metabolism
Immunoglobulin Fab Fragments - pharmacology
Models, Molecular
Multiprotein Complexes - chemistry
Multiprotein Complexes - genetics
Multiprotein Complexes - metabolism
Mutation, Missense
Oligomerization
Protein Binding
Protein Multimerization - drug effects
Protein Structure, Tertiary
Receptors, TNF-Related Apoptosis-Inducing Ligand - agonists
Receptors, TNF-Related Apoptosis-Inducing Ligand - chemistry
Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics
Stereoisomerism
T cell receptors
TRAIL protein
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Summary:The fully human monoclonal antibody KMTR2 acts as a strong direct agonist for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 2 (TRAIL-R2), which is capable of inducing apoptotic cell death without cross-linking. To investigate the mechanism of direct agonistic activity induced by KMTR2, the crystal structure of the extracellular region of TRAIL-R2 and a Fab fragment derived from KMTR2 (KMTR2-Fab) was determined to 2.1 Å resolution. Two KMTR2-Fabs assembled with the complementarity-determining region 2 of the light chain via two-fold crystallographic symmetry, suggesting that the KMTR2-Fab assembly tended to enhance TRAIL-R2 oligomerization. A single mutation at Asn53 to Arg located at the two-fold interface in the KMTR2 resulted in a loss of its apoptotic activity, although it retained its antigen-binding activity. These results indicate that the strong agonistic activity, such as apoptotic signaling and tumor regression, induced by KMTR2 is attributed to TRAIL-R2 superoligomerization induced by the interdimerization of KMTR2.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep17936