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Biological membrane interfaces involved in diseases: a biophysical study
Umeå University, Faculty of Science and Technology, Chemistry.
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Interactions between peptides and biological lipid membranes play a crucial role in many cellular processes such as in the mechanism behind Alzheimer’s disease where amyloid-beta peptide (Abeta)is thought to be a key component. The initial step of binding between a surface active peptide and its target membrane or membrane receptor can involve a non specific electrostatic association where positively charged amino acid residues and a negatively charged membrane surface interact. Here, the use of high resolution MAS NMR provides a highly sensitive and non perturbing way of studying the electrostatic potential present at lipid membrane surfaces and the changes resulting from the association of peptides. The interaction between pharmacologically relevant peptides and lipid membranes can also involve incorporation of the peptide into the membrane core and by complementing the NMR approach with differential scanning calorimetry (DSC) the hydrophobic incorporation can be studied in a non invasive way.

By using 14N MAS NMR on biological lipid systems for the first time, in addition to 31P, 2H NMR and differential scanning calorimetry (DSC), gives a full picture of the changes all along the phospholipid following interactions at the membrane interface region. Being able to

monitor the full length of the phospholipid enables us to differentiate between interactions related to either membrane surface association or hydrophobic core incorporation. This approach was used to establish that the interaction between nociceptin and negatively charged lipid membranes is electrostatic and hence that nociceptin can initially associate with a membrane surface before binding to its receptor. Also, it was found that Abeta can interact with phospholipid membranes via two types of interactions with fundamentally adverse effects. The results reveal that Abeta can associate with the surface of a neuronal membrane promoting accelerated aggregation of the peptide leading to neuronal apoptotic cell death. Furthermore it is also shown that Abeta can anchor itself into the membrane and suppress the neurotoxic aggregation of Abeta.

Place, publisher, year, edition, pages
Umeå: Kemi , 2006. , 50 p.
Keyword [en]
Solid-state NMR, DSC, Amyloid-beta peptide, Nociceptin, DMPC, DMPG, DDAB, peptide-lipid interaction, branched-chain fatty acid.
National Category
Physical Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-806ISBN: 91-7264-080-4 (print)OAI: oai:DiVA.org:umu-806DiVA: diva2:144622
Public defence
2006-09-15, KB3A9, KBC-huset, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2006-06-02 Created: 2006-06-02 Last updated: 2009-09-07Bibliographically approved
List of papers
1. Association of amyloid-β peptide with membrane surfaces monitored by solid state NMR
Open this publication in new window or tab >>Association of amyloid-β peptide with membrane surfaces monitored by solid state NMR
2002 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 4, no 22, 5524-5530 p.Article in journal (Refereed) Published
Abstract [en]

Amyloid-β peptide (Aβ), a key substance in Alzheimers disease (AD), is characterized by its abnormal folding into neurotoxic aggregates. Since Aβ comprises an extracellular and transmembrane domain, some of its neurotoxic actions might be exerted via interactions with neuronal membranes. Wideline and magic angle spinning 14N and 31P NMR have been used in combination with differential scanning calorimetry and circular dichroism spectroscopy to investigate the association between Aβ1–40 peptide and membranes with different electrostatic surface potentials. Calorimetric measurements showed that all membrane systems were in the liquid crystalline state at 308 K. Binding of Aβ1–40 at a 30 1 lipid/peptide ratio to membranes composed of neutral dimyristoyl-phosphatidylcholine (DMPC) and negatively charged dimyristoylphosphatidylglycerol (DMPG) at a 4 : 1 molar ratio is mainly driven electrostatically, reflected in characteristic changes of the isotropic 31P chemical shift values for both lipids. In addition, the average orientation of the choline headgroup of DMPC, with its electric P–N+(CH3)3 dipole, changed directly in response to the reduced negative membrane surface potential. The deviation in tilt angle of the PN vector relative to the membrane surface is manifested in the observed 14N NMR quadrupole splitting and can therefore be described semiquantitatively. Adding Aβ1–40 to membranes with nominal neutral surface charge, but composed of a ternary mixture of DMPC with DMPG and the cationic amphiphile didodecyldimethyl–ammonium bromide (DDAB) at a 3 : 1 : 1 molar ratio revealed surprisingly electrostatic interactions visible in the NMR spectra. Since Aβ1–40 does not bind to neutral DMPC bilayers a model is proposed, in which on a molecular level the charged residues of Aβ1–40 peptide can interact independently with lipid headgroups of various charges in these microscopically heterogeneous systems.

Identifiers
urn:nbn:se:umu:diva-5647 (URN)10.1039/b206351d (DOI)
Available from: 2007-01-16 Created: 2007-01-16 Last updated: 2017-12-14Bibliographically approved
2. Two Types of Alzheimer’s β-Amyloid (1–40) Peptide Membrane Interactions: Aggregation Preventing Transmembrane Anchoring Versus Accelerated Surface Fibril Formation
Open this publication in new window or tab >>Two Types of Alzheimer’s β-Amyloid (1–40) Peptide Membrane Interactions: Aggregation Preventing Transmembrane Anchoring Versus Accelerated Surface Fibril Formation
2004 (English)In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 335, no 4, 1039-1049 p.Article in journal (Refereed) Published
Abstract [en]

The 39–42 amino acid long, amphipathic amyloid-β peptide (Aβ) is one of the key components involved in Alzheimer's disease (AD). In the neuropathology of AD, Aβ presumably exerts its neurotoxic action via interactions with neuronal membranes. In our studies a combination of 31P MAS NMR (magic angle spinning nuclear magnetic resonance) and CD (circular dichroism) spectroscopy suggest fundamental differences in the functional organization of supramolecular Aβ1–40 membrane assemblies for two different scenarios with potential implication in AD: Aβ peptide can either be firmly anchored in a membrane upon proteolytic cleavage, thereby being prevented against release and aggregation, or it can have fundamentally adverse effects when bound to membrane surfaces by undergoing accelerated aggregation, causing neuronal apoptotic cell death. Acidic lipids can prevent release of membrane inserted Aβ1–40 by stabilizing its hydrophobic transmembrane C-terminal part (residue 29–40) in an α-helical conformation via an electrostatic anchor between its basic Lys28 residue and the negatively charged membrane interface. However, if Aβ1–40 is released as a soluble monomer, charged membranes act as two-dimensional aggregation-templates where an increasing amount of charged lipids (possible pathological degradation products) causes a dramatic accumulation of surface-associated Aβ1–40 peptide followed by accelerated aggregation into toxic structures. These results suggest that two different molecular mechanisms of peptide–membrane assemblies are involved in Aβ′s pathophysiology with the finely balanced type of Aβ–lipid interactions against release of Aβ from neuronal membranes being overcompensated by an Aβ–membrane assembly which causes toxic β-structured aggregates in AD. Therefore, pathological interactions of Aβ peptide with neuronal membranes might not only depend on the oligomerization state of the peptide, but also the type and nature of the supramolecular Aβ–membrane assemblies inherited from Aβ′s origin.

Keyword
lipid-membrane, β-amyloid peptide, peptide insertion, dircular dichroism, 31P MAS NMR
Identifiers
urn:nbn:se:umu:diva-5201 (URN)10.1016/j.jmb.2003.11.046 (DOI)
Available from: 2006-06-02 Created: 2006-06-02 Last updated: 2017-12-14Bibliographically approved
3. Molecular Insight into the Electrostatic Membrane Surface Potential by 14N/31P MAS NMR: Nociceptin-Lipid Association
Open this publication in new window or tab >>Molecular Insight into the Electrostatic Membrane Surface Potential by 14N/31P MAS NMR: Nociceptin-Lipid Association
2005 In: Journal of the American Chemical Society, ISSN 0002-7863, Vol. 127, no 18, 6610-6616 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-5202 (URN)
Available from: 2006-06-02 Created: 2006-06-02Bibliographically approved
4. Impact on Lipid Membrane Organization by Free Branched-Chain Fatty Acids
Open this publication in new window or tab >>Impact on Lipid Membrane Organization by Free Branched-Chain Fatty Acids
In: Physical Chemistry Chemical PhysicsArticle in journal (Refereed) Submitted
Identifiers
urn:nbn:se:umu:diva-5203 (URN)
Available from: 2006-06-02 Created: 2006-06-02Bibliographically approved

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