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Rational design of a stapled JAZ9 peptide inhibiting protein-protein interaction of a plant transcription factor.

ABSTRACT: We herein describe the development of a stapled peptide inhibitor for a jasmonate-related transcription factor. The designed peptide selectively inhibited MYCs, master-regulators of jasmonate signaling, and selectively suppressed MYC-mediated gene expression in Arabidopsis thaliana. It is proposed as a novel chemical tool for the analysis of MYC related jasmoante signaling.

SUBMITTER: Suzuki K

PROVIDER: S-EPMC8341433 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Rational design of a stapled JAZ9 peptide inhibiting protein-protein interaction of a plant transcription factor.

Suzuki Kaho K Takaoka Yousuke Y Ueda Minoru M

RSC chemical biology 20210105 2

We herein describe the development of a stapled peptide inhibitor for a jasmonate-related transcription factor. The designed peptide selectively inhibited MYCs, master-regulators of jasmonate signaling, and selectively suppressed MYC-mediated gene expression in <i>Arabidopsis thaliana</i>. It is proposed as a novel chemical tool for the analysis of MYC related jasmoante signaling. ...[more]

PMID: 34458795

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Project description:The ubiquitin-proteasome system is an essential regulator of many cellular processes including controlling protein homeostasis. The degradation of proteins by the multi-subunit proteasome complex is tightly regulated through a series of checkpoints, amongst which are a set of deubiquitinating proteases (DUBs). The proteasome-associated DUBs, UCH-L5 (Ubiquitin carboxyl-terminal hydrolase isozyme L5) and USP14 (Ubiquitin-specific protease 14), and the integral-DUB in the proteasome, Rpn11, is known to regulate proteasomal degradation by deubiquitination of distinct substrates. Although selective inhibitors for USP14 and Rpn11 have been recently developed, there are no known inhibitors that selectively bind to UCH-L5. The X-ray structure of the Ubiquitin (Ub) bound to UCH-L5 shows a β-sheet hairpin in Ub that contains a crucial hydrophobic patch involved in the interaction with UCH-L5. Herein, we designed and developed both a Ub sequence-based linear- and cyclic- β-sheet hairpin peptide that was found to preferably inhibit UCH-L5. We show that these peptides have low micromolar IC50 values and the cyclic peptide competes with the activity-based UbVME (Ubiquitin-Vinyl-Methyl-Ester) probe for UCH-L5, binding in a concentration-dependent manner. We further establish the selectivity profile of the cyclic peptide for UCH-L5 compared to other members of the UCH-DUB family and other cysteine DUBs in cell lysate. Furthermore, the cyclic peptide infiltrated cells resulting in the accumulation of polyUb chains, and was found to be non-toxic at the concentrations used here. Taken together, our data suggest that the cyclic peptide permeates the cell membrane, inhibits UCH-L5 by possibly blocking its deubiquitinating function, and contributes to the accumulation of polyubiquitinated substrates. The implications of inhibiting UCH-L5 in the context of the 26S proteasome render it an attractive candidate for further development as a potential selective inhibitor for therapeutic purposes.

Dataset Information

Rational design of a stapled JAZ9 peptide inhibiting protein-protein interaction of a plant transcription factor.

Publications

Rational design of a stapled JAZ9 peptide inhibiting protein-protein interaction of a plant transcription factor.

Similar Datasets

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