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HAMLET Forms Annular Oligomers When Deposited with Phospholipid Monolayers

Baumann, Anne; Gjerde, Anja Underhaug; Ying, Ming; Svanborg, Catharina LU ; Holmsen, Holm; Glomm, Wilhelm R.; Martinez, Aurora and Halskau, Oyvind (2012) In Journal of Molecular Biology 418(1-2). p.90-102
Abstract
Recently, the anticancer activity of human a-lactalbumin made lethal to tumor cells (HAMLET) has been linked to its increased membrane affinity in vitro, at neutral pH, and ability to cause leakage relative to the inactive native bovine alpha-lactalbumin (BLA) protein. In this study, atomic force microscopy resolved membrane distortions and annular oligomers (AOs) produced by HAMLET when deposited at neutral pH on mica together with a negatively charged lipid monolayer. BLA, BAMLET (HAMLET's bovine counterpart) and membrane-binding Peptide C, corresponding to BLA residues 75-100, also form AO-like structures under these conditions but at higher subphase concentrations than HAMLET. The N-terminal Peptide A, which binds to membranes at... (More)
Recently, the anticancer activity of human a-lactalbumin made lethal to tumor cells (HAMLET) has been linked to its increased membrane affinity in vitro, at neutral pH, and ability to cause leakage relative to the inactive native bovine alpha-lactalbumin (BLA) protein. In this study, atomic force microscopy resolved membrane distortions and annular oligomers (AOs) produced by HAMLET when deposited at neutral pH on mica together with a negatively charged lipid monolayer. BLA, BAMLET (HAMLET's bovine counterpart) and membrane-binding Peptide C, corresponding to BLA residues 75-100, also form AO-like structures under these conditions but at higher subphase concentrations than HAMLET. The N-terminal Peptide A, which binds to membranes at acidic but not at neutral pH, did not form AOs. This suggests a correlation between the capacity of the proteins/peptides to integrate into the membrane at neutral pH as observed by liposome content leakage and circular dichroism experiments and the formation of AOs, albeit at higher concentrations. Formation of AOs, which might be important to HAMLET's tumor toxic action, appears related to the increased tendency of the protein to populate intermediately folded states compared to the native protein, the formation of which is promoted by, but not uniquely dependent on, the oleic acid molecules associated with HAMLET. (C) 2012 Elsevier Ltd. All rights reserved. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
alpha-lactalbumin, membrane binding, pore formation, leakage, AFM
in
Journal of Molecular Biology
volume
418
issue
1-2
pages
90 - 102
publisher
Elsevier
external identifiers
  • wos:000302831000009
  • scopus:84858698801
ISSN
1089-8638
DOI
10.1016/j.jmb.2012.02.006
language
English
LU publication?
yes
id
9a677232-14a7-4a92-845f-efe6abae14b6 (old id 2571012)
date added to LUP
2012-06-01 08:53:01
date last changed
2017-04-23 04:05:40
@article{9a677232-14a7-4a92-845f-efe6abae14b6,
  abstract     = {Recently, the anticancer activity of human a-lactalbumin made lethal to tumor cells (HAMLET) has been linked to its increased membrane affinity in vitro, at neutral pH, and ability to cause leakage relative to the inactive native bovine alpha-lactalbumin (BLA) protein. In this study, atomic force microscopy resolved membrane distortions and annular oligomers (AOs) produced by HAMLET when deposited at neutral pH on mica together with a negatively charged lipid monolayer. BLA, BAMLET (HAMLET's bovine counterpart) and membrane-binding Peptide C, corresponding to BLA residues 75-100, also form AO-like structures under these conditions but at higher subphase concentrations than HAMLET. The N-terminal Peptide A, which binds to membranes at acidic but not at neutral pH, did not form AOs. This suggests a correlation between the capacity of the proteins/peptides to integrate into the membrane at neutral pH as observed by liposome content leakage and circular dichroism experiments and the formation of AOs, albeit at higher concentrations. Formation of AOs, which might be important to HAMLET's tumor toxic action, appears related to the increased tendency of the protein to populate intermediately folded states compared to the native protein, the formation of which is promoted by, but not uniquely dependent on, the oleic acid molecules associated with HAMLET. (C) 2012 Elsevier Ltd. All rights reserved.},
  author       = {Baumann, Anne and Gjerde, Anja Underhaug and Ying, Ming and Svanborg, Catharina and Holmsen, Holm and Glomm, Wilhelm R. and Martinez, Aurora and Halskau, Oyvind},
  issn         = {1089-8638},
  keyword      = {alpha-lactalbumin,membrane binding,pore formation,leakage,AFM},
  language     = {eng},
  number       = {1-2},
  pages        = {90--102},
  publisher    = {Elsevier},
  series       = {Journal of Molecular Biology},
  title        = {HAMLET Forms Annular Oligomers When Deposited with Phospholipid Monolayers},
  url          = {http://dx.doi.org/10.1016/j.jmb.2012.02.006},
  volume       = {418},
  year         = {2012},
}