Peer-Reviewed Journal Details
Mandatory Fields
Tur, V,van der Sloot, AM,Reis, CR,Szegezdi, E,Cool, RH,Samali, A,Serrano, L,Quax, WJ
2008
July
Journal Of Biological Chemistry
DR4-selective tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) variants obtained by structure-based design
Published
()
Optional Fields
RECEPTOR-SELECTIVE MUTANTS FADD-DEPENDENT APOPTOSIS NF-KAPPA-B COMPUTATIONAL REDESIGN MONOCLONAL-ANTIBODIES BINDING DEATH DR5 SPECIFICITY CASPASE-8
283
20560
20568
Tumor necrosis factor-related apoptosis-inducing ligand ( TRAIL) is a potential anticancer agent that selectively induces apoptosis in a variety of cancer cells by interacting with death receptors DR4 and DR5. TRAIL can also bind to decoy receptors ( DcR1, DcR2, and osteoprotegerin receptor) that cannot induce apoptosis. Different tumor types respond either to DR4 or to DR5 activation, and chemotherapeutic drugs can increase the expression of DR4 or DR5 in cancer cells. Thus, DR4 or DR5 receptor-specific TRAIL variants would permit new and tumor-selective therapies. Previous success in generating a DR5-selective TRAIL mutant using computer-assisted protein design prompted us to make a DR4-selective TRAIL variant. Technically, the design of DR4 receptor-selective TRAIL variants is considerably more challenging compared with DR5 receptor-selective variants, because of the lack of a crystal structure of the TRAIL-DR4 complex. A single amino acid substitution of Asp at residue position 218 of TRAIL to His or Tyr was predicted to have a favorable effect on DR4 binding specificity. Surface plasmon resonance-based receptor binding tests showed a lowered DR5 affinity in concert with increased DR4 specificity for the designed variants, D218H and D218Y. Binding to DcR1, DcR2, and osteoprotegerin was also decreased. Cell line assays confirmed that the variants could not induce apoptosis in DR5-responsive Jurkat and A2780 cells but were able to induce apoptosis in DR4-responsive EM-2 and ML-1 cells.
DOI 10.1074/jbc.M800457200
Grant Details
Publication Themes