title: Potentiation of TRAIL killing activity by multimerization through isoleucine zipper hexamerization motif.
abstract: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a homo-trimeric cytotoxic ligand. Several studies have demonstrated that incorporation of artificial trimerization motifs into the TRAIL protein leads to the enhancement of biological activity. Here, we show that linkage of the isoleucine zipper hexamerization motif to the N-terminus of TRAIL, referred as ILz(6):TRAIL, leads to multimerization of its trimeric form, which has higher cytotoxic activity compared to its native state. Size exclusion chromatography of ILz(6):TRAIL revealed possible existence of various forms such as trimeric, hexameric, and multimeric (possibly containing one-, two-, and multi-units of trimeric TRAIL, respectively). Increased number of multimerized ILz(6):TRAIL units corresponded with enhanced cytotoxic activity. Further, a high degree of ILz(6):TRAIL multimerization triggered rapid signaling events such as activation of caspases, tBid generation, and chromatin condensation. Taken together, these results indicate that multimerization of TRAIL significantly enhances its cytotoxic activity. [BMB Reports 2016; 49(5): 282-287].
authors.affiliation: Departments of Biochemistry, Chosun University School of Medicine, Gwangju 61452, Korea.
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Han
authors.affiliation: Departments of Biochemistry, Chosun University School of Medicine, Gwangju 61452, Korea.
authors.forename: Ae Ran
authors.initials: AR
authors.lastname: Moon
authors.affiliation: Departments of Surgery, Chosun University School of Medicine, Gwangju 61452, Korea.
authors.forename: Jeong Hwan
authors.initials: JH
authors.lastname: Chang
authors.affiliation: School of Pharmacy, Chung-Ang University, Seoul 06974, Korea.
authors.forename: Jeehyeon
authors.initials: J
authors.lastname: Bae
authors.affiliation: Departments of Cellular and Molecular Medicine, Chosun University School of Medicine, Gwangju 61452, Korea.
authors.forename: Jin Myung
authors.initials: JM
authors.lastname: Choi
authors.affiliation: Departments of Cellular and Molecular Medicine, Chosun University School of Medicine, Gwangju 61452, Korea.
authors.forename: Sung Haeng
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Departments of Biochemistry, Chosun University School of Medicine, Gwangju 61452, Korea.
authors.forename: Tae-Hyoung
authors.initials: TH
authors.lastname: Kim
mesh_terms: D020816:Amino Acid Motifs; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007532:Isoleucine / Q000737:chemistry*; D019169:Jurkat Cells; D055503:Protein Multimerization; D011994:Recombinant Proteins / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
chemical_list: D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D007532:Isoleucine