Inhibition of LtxA Toxicity by Blocking Cholesterol Binding With Peptides

Loading...
Thumbnail Image
Penn collection
Departmental Papers (Dental)
Degree type
Discipline
Subject
Aggregatibacter actinomycetemcomitans
leukotoxin (LtxA)
cholesterol-binding
cholesterol recognition amino acid consensus (CRAC) motif
Dentistry
Funder
Grant number
License
Copyright date
Distributor
Related resources
Author
Brown, Angela C.
Koufos, Evan
Balashova, Nataliya
Lally, Edward T.
Balashova, Nataliya
Boesze-Battaglia, Kathleen
Lally, Edward T.
Contributor
Abstract

The leukotoxin (LtxA) produced by Aggregatibacter actinomycetemcomitans kills host immune cells, allowing the bacterium to establish an ecological niche in the upper aerodigestive tract of its human host. The interaction of LtxA with human immune cells is both complex and multifaceted, involving membrane lipids as well as cell-surface proteins. In the initial encounter with the host cell, LtxA associates with lymphocyte function-associated antigen-1 (LFA-1), a cell surface adhesion glycoprotein. However, we have also demonstrated that the toxin associates strongly with the plasma membrane lipids, specifically cholesterol. This association with cholesterol is regulated by a cholesterol recognition amino acid consensus (CRAC) motif, with a sequence of 334LEEYSKR340, in the N-terminal region of the toxin. Here, we have demonstrated that removal of cholesterol from the plasma membrane or mutation of the LtxA CRAC motif inhibits the activity of the toxin in THP-1 cells. To inhibit LtxA activity, we designed a short peptide corresponding to the CRAC336 motif of LtxA (CRAC336WT). This peptide binds to cholesterol and thereby inhibits the toxicity of LtxA in THP-1 cells. Previously, we showed that this peptide inhibits LtxA toxicity against Jn.9 (Jurkat) cells, indicating that peptides derived from the cholesterol-binding site of LtxA may have a potential clinical applicability in controlling infections of RTX-producing organisms.

Advisor
Date Range for Data Collection (Start Date)
Date Range for Data Collection (End Date)
Digital Object Identifier
Series name and number
Publication date
2016-02-01
Journal title
Molecular Oral Microbiology
Volume number
Issue number
Publisher
Publisher DOI
Journal Issue
Comments
Recommended citation
Collection