HAMLET interacts with lipid membranes and perturbs their structure and integrity.

HAMLET interacts with lipid membranes and perturbs their structure and integrity.

<h4>Background</h4>Cell membrane interactions rely on lipid bilayer constituents and molecules inserted within the membrane, including specific receptors. HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a tumoricidal complex of partially unfolded alpha-lactalbumin (HLA) an...

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Autores principales: Ann-Kristin Mossberg, Maja Puchades, Øyvind Halskau, Anne Baumann, Ingela Lanekoff, Yinxia Chao, Aurora Martinez, Catharina Svanborg, Roger Karlsson
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Lenguaje:EN
Publicado: Public Library of Science (PLoS) 2010
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Science
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Acceso en línea:https://doaj.org/article/963a6a80c65e4305a3df60dc5624ad54
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spelling oai:doaj.org-article:963a6a80c65e4305a3df60dc5624ad542021-11-25T06:25:36ZHAMLET interacts with lipid membranes and perturbs their structure and integrity.1932-620310.1371/journal.pone.0009384https://doaj.org/article/963a6a80c65e4305a3df60dc5624ad542010-02-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20186341/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Cell membrane interactions rely on lipid bilayer constituents and molecules inserted within the membrane, including specific receptors. HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a tumoricidal complex of partially unfolded alpha-lactalbumin (HLA) and oleic acid that is internalized by tumor cells, suggesting that interactions with the phospholipid bilayer and/or specific receptors may be essential for the tumoricidal effect. This study examined whether HAMLET interacts with artificial membranes and alters membrane structure.<h4>Methodology/principal findings</h4>We show by surface plasmon resonance that HAMLET binds with high affinity to surface adherent, unilamellar vesicles of lipids with varying acyl chain composition and net charge. Fluorescence imaging revealed that HAMLET accumulates in membranes of vesicles and perturbs their structure, resulting in increased membrane fluidity. Furthermore, HAMLET disrupted membrane integrity at neutral pH and physiological conditions, as shown by fluorophore leakage experiments. These effects did not occur with either native HLA or a constitutively unfolded Cys-Ala HLA mutant (rHLA(all-Ala)). HAMLET also bound to plasma membrane vesicles formed from intact tumor cells, with accumulation in certain membrane areas, but the complex was not internalized by these vesicles or by the synthetic membrane vesicles.<h4>Conclusions/significance</h4>The results illustrate the difference in membrane affinity between the fatty acid bound and fatty acid free forms of partially unfolded HLA and suggest that HAMLET engages membranes by a mechanism requiring both the protein and the fatty acid. Furthermore, HAMLET binding alters the morphology of the membrane and compromises its integrity, suggesting that membrane perturbation could be an initial step in inducing cell death.Ann-Kristin MossbergMaja PuchadesØyvind HalskauAnne BaumannIngela LanekoffYinxia ChaoAurora MartinezCatharina SvanborgRoger KarlssonPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 2, p e9384 (2010)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Ann-Kristin Mossberg
Maja Puchades
Øyvind Halskau
Anne Baumann
Ingela Lanekoff
Yinxia Chao
Aurora Martinez
Catharina Svanborg
Roger Karlsson
HAMLET interacts with lipid membranes and perturbs their structure and integrity.
description <h4>Background</h4>Cell membrane interactions rely on lipid bilayer constituents and molecules inserted within the membrane, including specific receptors. HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a tumoricidal complex of partially unfolded alpha-lactalbumin (HLA) and oleic acid that is internalized by tumor cells, suggesting that interactions with the phospholipid bilayer and/or specific receptors may be essential for the tumoricidal effect. This study examined whether HAMLET interacts with artificial membranes and alters membrane structure.<h4>Methodology/principal findings</h4>We show by surface plasmon resonance that HAMLET binds with high affinity to surface adherent, unilamellar vesicles of lipids with varying acyl chain composition and net charge. Fluorescence imaging revealed that HAMLET accumulates in membranes of vesicles and perturbs their structure, resulting in increased membrane fluidity. Furthermore, HAMLET disrupted membrane integrity at neutral pH and physiological conditions, as shown by fluorophore leakage experiments. These effects did not occur with either native HLA or a constitutively unfolded Cys-Ala HLA mutant (rHLA(all-Ala)). HAMLET also bound to plasma membrane vesicles formed from intact tumor cells, with accumulation in certain membrane areas, but the complex was not internalized by these vesicles or by the synthetic membrane vesicles.<h4>Conclusions/significance</h4>The results illustrate the difference in membrane affinity between the fatty acid bound and fatty acid free forms of partially unfolded HLA and suggest that HAMLET engages membranes by a mechanism requiring both the protein and the fatty acid. Furthermore, HAMLET binding alters the morphology of the membrane and compromises its integrity, suggesting that membrane perturbation could be an initial step in inducing cell death.
format article
author Ann-Kristin Mossberg
Maja Puchades
Øyvind Halskau
Anne Baumann
Ingela Lanekoff
Yinxia Chao
Aurora Martinez
Catharina Svanborg
Roger Karlsson
author_facet Ann-Kristin Mossberg
Maja Puchades
Øyvind Halskau
Anne Baumann
Ingela Lanekoff
Yinxia Chao
Aurora Martinez
Catharina Svanborg
Roger Karlsson
author_sort Ann-Kristin Mossberg
title HAMLET interacts with lipid membranes and perturbs their structure and integrity.
title_short HAMLET interacts with lipid membranes and perturbs their structure and integrity.
title_full HAMLET interacts with lipid membranes and perturbs their structure and integrity.
title_fullStr HAMLET interacts with lipid membranes and perturbs their structure and integrity.
title_full_unstemmed HAMLET interacts with lipid membranes and perturbs their structure and integrity.
title_sort hamlet interacts with lipid membranes and perturbs their structure and integrity.
publisher Public Library of Science (PLoS)
publishDate 2010
url https://doaj.org/article/963a6a80c65e4305a3df60dc5624ad54
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