Role of single disulfide linkages in the folding and activity of scyllatoxin-based BH3 domain mimetics.
Anti-apoptotic Bcl-2 proteins are implicated in pathogenic cell survival and have attracted considerable interest as therapeutic targets. We recently developed a class of synthetic peptide based on scyllatoxin (ScTx) designed to mimic the helical BH3 interaction domain of the pro-apoptotic Bcl-2 protein Bax. In this communication, the contribution of single disulfides in the folding and function of ScTx-Bax peptides was investigated. We synthesized five ScTx-Bax variants, each presenting a different combination of native disulfide linkage and evaluated their ability to directly bind Bcl-2 in vitro. It was determined that the position of the disulfide linkage had significant implications on the structure and function of ScTx-Bax peptides. This study underscores the importance of structural dynamics in BH3:Bcl-2 interactions and further validates ScTx-based ligands as potential modulators of anti-apoptotic Bcl-2 function. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.
Department of Chemistry and Biochemistry, Ohio University, Athens, OH, 45701, USA.
Danushka
D
Arachchige
Department of Chemistry and Biochemistry, Ohio University, Athens, OH, 45701, USA.
M
M
Margaret Harris
Department of Chemistry and Biochemistry, Ohio University, Athens, OH, 45701, USA.
Zachary
Z
Coon
Department of Chemistry and Biochemistry, Ohio University, Athens, OH, 45701, USA.
Jacob
J
Carlsen
Department of Chemistry and Biochemistry, Ohio University, Athens, OH, 45701, USA.|Edison Biotechnology Institute, Ohio University, Athens, OH, 45701, USA.|Molecular and Cellular Biology Program, Ohio University, Athens, OH, 45701, USA.
Justin M
http://orcid.org/0000-0001-6040-1277
JM
Holub
D040761:Biomimetic Materials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004220:Disulfides / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D017510:Protein Folding; D017433:Protein Structure, Secondary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000378:metabolism*; D012604:Scorpion Venoms / Q000737:chemistry / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000737:chemistry
C494826:BAX protein, human; D004220:Disulfides; D019253:Proto-Oncogene Proteins c-bcl-2; D012604:Scorpion Venoms; D051028:bcl-2-Associated X Protein; C056574:leiurotoxin I
BH3 domain mimetic; anti-apoptotic Bcl-2 proteins; apoptosis; disulfide linkage; ligand binding; scyllatoxin