PMID: 8962072Dec 10, 1996Paper

Dominant negative inhibition by fragments of a monomeric enzyme

Proceedings of the National Academy of Sciences of the United States of America
J E MichaelsW T Miller

Abstract

Dominant negative inhibition is most commonly seen when a mutant subunit of a multisubunit protein is coexpressed with the wild-type protein so that assembly of a functional oligomer is impaired. By analogy, it should be possible to interfere with the functional assembly of a monomeric enzyme by interfering with the folding pathway. Experiments in vitro by others suggested that fragments of a monomeric enzyme might be exploited for this purpose. We report here dominant negative inhibition of bacterial cell growth by expression of fragments of a tRNA synthetase. Inhibition is fragment-specific, as not all fragments cause inhibition. An inhibitory fragment characterized in more detail forms a specific complex with the intact enzyme in vivo, leading to enzyme inactivation. This fragment also associated stoichiometrically with the full-length enzyme in vitro after denaturation and refolding, and the resulting complex was catalytically inactive. Inhibition therefore appears to arise from an interruption in the folding pathway of the wild-type enzyme, thus suggesting a new strategy to design dominant negative inhibitors of monomeric enzymes.

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Citations

Oct 29, 1998·Protein Science : a Publication of the Protein Society·G KernS Marqusee
Oct 15, 1998·Proceedings of the National Academy of Sciences of the United States of America·J N PelletierS W Michnick
Feb 17, 2001·American Journal of Physiology. Heart and Circulatory Physiology·P KometianiF K Askari
Apr 10, 2019·Nature Methods·Michael W DorrityStanley Fields
Feb 25, 1998·Biochemical and Biophysical Research Communications·S J Kim, S Kim

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