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Journal article
Cytolethal Distending Toxin-induced Cell Cycle Arrest of Lymphocytes Is Dependent upon Recognition and Binding to Cholesterol
The Journal of biological chemistry, v 284(16), pp 10650-10658
17 Apr 2009
PMID: 19240023
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Induction of cell cycle arrest in lymphocytes after exposure to the
Aggregatibacter actinomycetemcomitans
cytolethal distending toxin
(Cdt) is dependent upon the integrity of lipid membrane microdomains. In this
study we further demonstrate that the association of Cdt with lymphocyte
plasma membranes is dependent upon binding to cholesterol. Depletion of
cholesterol resulted in reduced toxin binding, whereas repletion of
cholesterol-depleted cells restored binding. We employed fluorescence
resonance energy transfer and surface plasmon resonance to demonstrate that
toxin association with model membranes is dependent upon the concentration of
cholesterol; moreover, these interactions were cholesterol-specific as the
toxin failed to interact with model membranes containing stigmasterol,
ergosterol, or lanosterol. Further analysis of the toxin indicated that the
CdtC subunit contains a cholesterol recognition/interaction amino acid
consensus (CRAC) region. Mutation of the CRAC site resulted in decreased
binding of the holotoxin to cholesterol-containing model membranes as well as
to the surface of Jurkat cells. The mutant toxin also exhibited reduced
capacity for intracellular transfer of the active toxin subunit, CdtB, as well
as reduced toxicity. Collectively, these observations indicate that membrane
cholesterol serves as an essential ligand for Cdt and that this association
can be blocked by either depleting membranes of cholesterol or mutation of the
CRAC site.
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Details
- Title
- Cytolethal Distending Toxin-induced Cell Cycle Arrest of Lymphocytes Is Dependent upon Recognition and Binding to Cholesterol
- Creators
- Kathleen Boesze-Battaglia - University of PennsylvaniaAngela Brown - University of PennsylvaniaLisa Walker - University of PennsylvaniaDave Besack - University of PennsylvaniaAli Zekavat - University of PennsylvaniaSteve Wrenn - Drexel UniversityClaude Krummenacher - Drexel UniversityBruce J. Shenker - University of Pennsylvania
- Publication Details
- The Journal of biological chemistry, v 284(16), pp 10650-10658
- Publisher
- American Society for Biochemistry and Molecular Biology
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Chemical and Biological Engineering
- Web of Science ID
- WOS:000265104600039
- Scopus ID
- 2-s2.0-67449090254
- Other Identifier
- 991019182658504721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology