Journal Article

Improved cytotoxicity of novel TRAIL variants produced as recombinant fusion proteins

Małgorzata Figiel, Piotr Bonarek, Andrzej Górecki, Sebastian D Pawlak, Bartłomiej Żerek, Beata Chęcińska, Jerzy Pieczykolan and Marta Dziedzicka-Wasylewska

in Protein Engineering, Design and Selection

Volume 31, issue 2, pages 37-46
Published in print February 2018 | ISSN: 1741-0126
Published online January 2018 | e-ISSN: 1741-0134 | DOI: https://dx.doi.org/10.1093/protein/gzx065
Improved cytotoxicity of novel TRAIL variants produced as recombinant fusion proteins

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Abstract

The TNF-Related Apoptosis Inducing Ligand (TRAIL) cytokine triggers apoptosis specifically in cancer cells. Susceptibility of a given cell to TRAIL depends on the activity of regulatory proteins, one of the most important of which is BID. The aim of this study was to increase the cytotoxic potential of TRAIL against cancer cells. TRAIL was fused to the BH3 domain of BID. Hence, TRAIL acted not only as an anticancer agent, but also as a specific carrier for the BID fragment. Two fusion protein variants were obtained by genetic engineering, harboring two different linker sequences. The short linker allowed both parts of the fusion protein to fold into their native structures. The long linker influenced the structure of the fused proteins but nonetheless resulted in their highest cytotoxic activity. Optimal buffer formulation was determined for all the analyzed TRAIL variants. Fusing the BH3 domain of BID to TRAIL improved the cytotoxic potential of TRAIL. Further, these findings may be useful for the optimization of other anticancer drugs based on TRAIL, since the appropriate formulation would secure their native structures during prolonged storage.

Keywords: cancer-specific cytotoxicity; fusion protein; optimal formulation; protein stability assessment; TRAIL

Journal Article.  6717 words.  Illustrated.

Subjects: Proteins

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