Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/161263
Title: Roseltide rT7 is a disulfide-rich, anionic, and cell-penetrating peptide that inhibits proteasomal degradation
Authors: Kam, Antony 
Loo, Shining
Fan, Jing-Song
Sze, Siu Kwan
Yang, Daiwen
Tam, James P.
Keywords: Science::Biological sciences
Issue Date: 2019
Source: Kam, A., Loo, S., Fan, J., Sze, S. K., Yang, D. & Tam, J. P. (2019). Roseltide rT7 is a disulfide-rich, anionic, and cell-penetrating peptide that inhibits proteasomal degradation. Journal of Biological Chemistry, 294(51), 19604-19615. https://dx.doi.org/10.1074/jbc.RA119.010796
Project: MOE2016-T3-1-003 
Journal: Journal of Biological Chemistry 
Abstract: Disulfide-rich plant peptides with molecular masses of 2-6 kDa represent an expanding class of peptidyl-type natural products with diverse functions. They are structurally compact, hyperstable, and underexplored as cell-penetrating agents that inhibit intracellular functions. Here, we report the discovery of an anionic, 34-residue peptide, the disulfide-rich roseltide rT7 from Hibiscus sabdariffa (of the Malvaceae family) that penetrates cells and inhibits their proteasomal activities. Combined proteomics and NMR spectroscopy revealed that roseltide rT7 is a cystine-knotted, six-cysteine hevein-like cysteine-rich peptide. A pair-wise comparison indicated that roseltide rT7 is >100-fold more stable against protease degradation than its S-alkylated analog. Confocal microscopy studies and cell-based assays disclosed that after roseltide rT7 penetrates cells, it causes accumulation of ubiquitinated proteins, inhibits human 20S proteasomes, reduces tumor necrosis factor-induced IκBα degradation, and decreases expression levels of intercellular adhesion molecule-1. Structure-activity studies revealed that roseltide rT7 uses a canonical substrate-binding mechanism for proteasomal inhibition enabled by an IIML motif embedded in its proline-rich and exceptionally long intercysteine loop 4. Taken together, our results provide mechanistic insights into a novel disulfide-rich, anionic, and cell-penetrating peptide, representing a potential lead for further development as a proteasomal inhibitor in anti-cancer or anti-inflammatory therapies.
URI: https://hdl.handle.net/10356/161263
ISSN: 0021-9258
DOI: 10.1074/jbc.RA119.010796
Schools: School of Biological Sciences 
Rights: © 2019 Kam et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc. This is an open access article under the CC BY license.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SBS Journal Articles

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