TRAIL-R2 Superoligomerization Induced by Human Monoclonal Agonistic Antibody KMTR2.
Sci Rep
; 5: 17936, 2015 Dec 17.
Article
in En
| MEDLINE
| ID: mdl-26672965
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.
Full text:
1
Database:
MEDLINE
Main subject:
Receptors, TNF-Related Apoptosis-Inducing Ligand
/
Protein Multimerization
/
Antibodies, Monoclonal
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Sci Rep
Year:
2015
Type:
Article
Affiliation country:
Japan