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Aisenbrey, Christopher
Publications (9 of 9) Show all publications
Bugaytsova, J. A., Björnham, O., Chernov, Y. A., Gideonsson, P., Henriksson, S., Mendez, M., . . . Boren, T. (2017). Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence. Cell Host and Microbe, 21(3), 376-389
Open this publication in new window or tab >>Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence
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2017 (English)In: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 21, no 3, p. 376-389Article in journal (Refereed) Published
Abstract [en]

The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive-binding is reduced at low pH and restored by acid neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions and evolves during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers. We propose that BabA's extraordinary reversible acid responsiveness enables tight mucosal bacterial adherence while also allowing an effective escape from epithelial cells and mucus that are shed into the acidic bactericidal lumen and that bio-selection and changes in BabA binding properties through mutation and recombination with babA-related genes are selected by differences among individuals and by changes in gastric acidity over time. These processes generate diverse H. pylori subpopulations, in which BabA's adaptive evolution contributes to H. pylori persistence and overt gastric disease.

Place, publisher, year, edition, pages
CELL PRESS, 2017
National Category
Microbiology in the medical area Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-132788 (URN)10.1016/j.chom.2017.02.013 (DOI)000396375600023 ()28279347 (PubMedID)
Available from: 2017-05-11 Created: 2017-05-11 Last updated: 2019-05-24Bibliographically approved
Byström, R., Aisenbrey, C., Borowik, T., Bokvist, M., Lindström, F., Sani, M.-A., . . . Gröbner, G. (2008). Disordered proteins: Biological membranes as two-dimensional aggregation matrices. Cell Biochemistry and Biophysics, 52(3), 175-189
Open this publication in new window or tab >>Disordered proteins: Biological membranes as two-dimensional aggregation matrices
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2008 (English)In: Cell Biochemistry and Biophysics, ISSN 1085-9195, E-ISSN 1559-0283, Vol. 52, no 3, p. 175-189Article, review/survey (Refereed) Published
Abstract [en]

Aberrant folded proteins and peptides are hallmarks of amyloidogenic diseases. However, the molecular processes that cause these proteins to adopt non-native structures in vivo and become cytotoxic are still largely unknown, despite intense efforts to establish a general molecular description of their behavior. Clearly, the fate of these proteins is ultimately linked to their immediate biochemical environment in vivo. In this review, we focus on the role of biological membranes, reactive interfaces that not only affect the conformational stability of amyloidogenic proteins, but also their aggregation rates and, probably, their toxicity. We first provide an overview of recent work, starting with findings regarding the amphiphatic amyloid-β protein (Aβ), which give evidence that membranes can directly promote aggregation, and that the effectiveness in this process can be related to the presence of specific neuronal ganglioside lipids. In addition, we discuss the implications of recent research (medin as an detailed example) regarding putative roles of membranes in the misfolding behavior of soluble, non-amphiphatic proteins, which are attracting increasing interest. The potential role of membranes in exerting the toxic action of misfolded proteins will also be highlighted in a molecular context. In this review, we discuss novel NMR-based approaches for exploring membrane–protein interactions, and findings obtained using them, which we use to develop a molecular concept to describe membrane-mediated protein misfolding as a quasi-two-dimensional process rather than a three-dimensional event in a biochemical environment. The aim of the review is to provide researchers with a general understanding of the involvement of membranes in folding/misfolding processes in vivo, which might be quite universal and important for future research concerning amyloidogenic and misfolding proteins, and possible ways to prevent their toxic actions.

Keywords
Membranes, Surface, Amyloid, Aggregation, NMR
Identifiers
urn:nbn:se:umu:diva-10887 (URN)10.1007/s12013-008-9033-4 (DOI)
Available from: 2008-12-02 Created: 2008-12-02 Last updated: 2018-06-09Bibliographically approved
diva2:145793
Open this publication in new window or tab >>How is protein aggregation in amyloidogenic diseases modulated by biological membranes?
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2008 (English)In: European Biophysics Journal, ISSN 0175-7571, E-ISSN 1432-1017, European Biophysics Journal, ISSN 1432-1017 (Online), Vol. 37, no 3, p. 247-55Article in journal (Refereed) Published
Abstract [en]

The fate of proteins with amyloidogenic properties depends critically on their immediate biochemical environment. However, the role of biological interfaces such as membrane surfaces, as promoters of pathological aggregation of amyloidogenic proteins, is rarely studied and only established for the amyloid-β protein (Aβ) involved in Alzheimer’s disease, and α-synuclein in Parkinsonism. The occurrence of binding and misfolding of these proteins on membrane surfaces, is poorly understood, not at least due to the two-dimensional character of this event. Clearly, the nature of the folding pathway for Aβ protein adsorbed upon two-dimensional aggregation templates, must be fundamentally different from the three-dimensional situation in solution. Here, we summarize the current research and focus on the function of membrane interfaces as aggregation templates for amyloidogenic proteins (and even prionic ones). One major aspect will be the relationship between membrane properties and protein association and the consequences for amyloidogenic products. The other focus will be on a general understanding of protein folding pathways on two-dimensional templates on a molecular level. Finally, we will demonstrate the potential importance of membrane-mediated aggregation for non-amphiphatic soluble amyloidogenic proteins, by using the SOD1 protein involved in the amyotrophic lateral sclerosis syndrome.

Place, publisher, year, edition, pages
SpringerLink, 2008
Identifiers
urn:nbn:se:umu:diva-6125 (URN)10.1007/s00249-007-0237-0 (DOI)18030461 (PubMedID)
Available from: 2008-02-26 Created: 2008-02-26 Last updated: 2018-06-09Bibliographically approved
Aisenbrey, C., Bechinger, B. & Gröbner, G. (2008). Macromolecular Crowding at Membrane Interfaces: Adsorption and Alignment of Membrane Peptides. Journal of Molecular Biology, 375, 376-385
Open this publication in new window or tab >>Macromolecular Crowding at Membrane Interfaces: Adsorption and Alignment of Membrane Peptides
2008 (English)In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 375, p. 376-385Article in journal (Refereed) Published
Abstract [en]

Association of proteins to cellular membranes is involved in various biological processes. Various theoretical models have been developed to describe this adsorption mechanism, commonly implying the concept of an ideal solution. However, due to the two-dimensional character of membrane surfaces intermolecular interactions between the adsorbed molecules become important. Therefore previously adsorbed molecules can influence the adsorption behavior of additional protein molecules and their membrane-associated structure. Using the model peptide LAH4, which upon membrane-adsorption can adopt a transmembrane as well as an in-planar configuration, we carried out a systematic study of the correlation between the peptide concentration in the membrane and the topology of this membrane-associated polypeptide. We could describe the observed binding behavior by establishing a concept, which includes intermolecular interactions in terms of a scaled particle theory.

High surface concentration of the peptide shifts the molecules from an in-planar into a transmembrane conformation, a process driven by the reduction of occupied surface area per molecule. In a cellular context, the crowding-dependent alignment might provide a molecular switch for a cell to sense and control its membrane occupancy. Furthermore, crowding might have pronounced effects on biological events, such as the cooperative behavior of antimicrobial peptides and the membrane triggered aggregation of amyloidogenic peptides.

Place, publisher, year, edition, pages
Elsevier, 2008
Keywords
peptide-lipid interactions, macromolecular crowding, lipid membranes, surface crowding, antibiotic peptides
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-6126 (URN)10.1016/j.jmb.2007.10.053 (DOI)000252103700006 ()18022193 (PubMedID)
Available from: 2007-12-07 Created: 2007-12-07 Last updated: 2019-07-08Bibliographically approved
diva2:149328
Open this publication in new window or tab >>Specific Isotope Labeling of Colicin E1 and B Channel Domains For Membrane Topological Analysis by Oriented Solid-State NMR Spectroscopy
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2008 (English)In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 9, no 6, p. 944-951Article in journal (Refereed) Published
Abstract [en]

An approach is presented to selectively label the methionines of the colicin E1 and B channel domains, each about 200 residues in size, and use them for oriented solid-state NMR investigations. By combining site-directed mutagenesis, bacterial overexpression in a methionine auxotroph E. coli strain and biochemical purification, quantitative amounts of the proteins for NMR structural investigations were obtained. The proteins were selectively labeled with 15N at only one, or at a few, selected sites. Multidimensional heteronuclear correlation high-resolution NMR spectroscopy and mass spectrometry were used to monitor the quality of isotopic labeling. Thereafter the proteins were reconstituted into oriented phospholipid bilayers and investigated by proton-decoupled 15N solid-state NMR spectroscopy. The colicin E1 thermolytic fragment that carries a single 15N methionine within its hydrophobic helix 9 region exhibited 15N resonances that are characteristic of helices that are oriented predominantly parallel to the membrane surface at low temperature, and a variety of alignments and conformations at room temperature. This suggests that the protein can adopt both umbrella and pen-knife conformations.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2008
Keywords
Bcl-2 proteins, isotopic labeling, membrane proteins, NMR spectroscopy, transmembrane helical loop
National Category
Biochemistry and Molecular Biology Physical Chemistry
Identifiers
urn:nbn:se:umu:diva-9657 (URN)10.1002/cbic.200700507 (DOI)000255348800017 ()18338351 (PubMedID)
Available from: 2008-05-08 Created: 2008-05-08 Last updated: 2019-08-07Bibliographically approved
Aisenbrey, C., Sudheendra, U. S., Ridley, H., Bertani, P., Marquette, A., Nedelkina, S., . . . Bechinger, B. (2007). Helix orientations in membrane-associated Bcl-XL determined by 15N-solid-state NMR spectroscopy. European Biophysics Journal, 37(1), 71-80
Open this publication in new window or tab >>Helix orientations in membrane-associated Bcl-XL determined by 15N-solid-state NMR spectroscopy
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2007 (English)In: European Biophysics Journal, ISSN 0175-7571 (Print) 1432-1017 (Online), Vol. 37, no 1, p. 71-80Article in journal (Refereed) Published
Abstract [en]

Controlled cell death is fundamental to tissue hemostasis and apoptosis malfunctions can lead to a wide range of diseases. Bcl-xL is an anti-apoptotic protein the function of which is linked to its reversible interaction with mitochondrial outer membranes. Its interfacial and intermittent bilayer association makes prediction of its bound structure difficult without using methods able to extract data from dynamic systems. Here we investigate Bcl-xL associated with oriented lipid bilayers at physiological pH using solid-state NMR spectroscopy. The data are consistent with a C-terminal transmembrane anchoring sequence and an average alignment of the remaining helices, i.e. including helices 5 and 6, approximately parallel to the membrane surface. Data from several biophysical approaches confirm that after removal of the C-terminus from Bcl-xL its membrane interactions are weak. In the presence of membranes Bcl-xL can still interact with a Bak BH3 domain peptide suggesting a model where the hydrophobic C-terminus of the protein unfolds and inserts into the membrane. During this conformational change the Bcl-xL hydrophobic binding pocket becomes accessible for protein–protein interactions whilst the structure of the N-terminal region remains intact.

Keywords
Membrane protein structure, Oriented lipid bilayer, Helix tilt angle, Topology, Apoptosis, Cancer, Protein–protein interactions
Identifiers
urn:nbn:se:umu:diva-14191 (URN)doi:10.1007/s00249-007-0165-z (DOI)
Note
Subject Collection Physics and AstronomyAvailable from: 2007-12-06 Created: 2007-12-06 Last updated: 2018-06-09Bibliographically approved
Aisenbrey, C., Bertani, P., Henklein, P. & Bechinger, B. (2007). Structure, dynamics and topology of membrane polypeptides by oriented 2H solid-state NMR spectroscopy. European Biophysics Journal, 36(4-5), 451-60
Open this publication in new window or tab >>Structure, dynamics and topology of membrane polypeptides by oriented 2H solid-state NMR spectroscopy
2007 (English)In: European Biophysics Journal, ISSN 0175-7571 (Print) 1432-1017 (Online), Vol. 36, no 4-5, p. 451-60Article in journal (Refereed) Published
Abstract [en]

Knowledge of the structure, dynamics and interactions of polypeptides when associated with phospholipid bilayers is key to understanding the functional mechanisms of channels, antibiotics, signal- or translocation peptides. Solid-state NMR spectroscopy on samples uniaxially aligned relative to the magnetic field direction offers means to determine the alignment of polypeptide bonds and domains relative to the bilayer normal. Using this approach the 15N chemical shift of amide bonds provides a direct indicator of the approximate helical tilt, whereas the 2H solid-state NMR spectra acquired from peptides labelled with 3,3,3-2H3-alanines contain valuable complimentary information for a more accurate analysis of tilt and rotation pitch angles. The deuterium NMR line shapes are highly sensitive to small variations in the alignment of the Cα–Cβ bond relative to the magnetic field direction and, therefore, also the orientational distribution of helices relative to the membrane normal. When the oriented membrane samples are investigated with their normal perpendicular to the magnetic field direction, the rate of rotational diffusion can be determined in a semi-quantitative manner and thereby the aggregation state of the peptides can be analysed. Here the deuterium NMR approach is first introduced showing results from model amphipathic helices. Thereafter investigations of the viral channel peptides Vpu1–27 and Influenza A M222–46 are shown. Whereas the 15N chemical shift data confirm the transmembrane helix alignments of these hydrophobic sequences, the deuterium spectra indicate considerable mosaic spread in the helix orientations. At least two peptide populations with differing rotational correlation times are apparent in the deuterium spectra of the viral channels suggesting an equilibrium between monomeric peptides and oligomeric channel configurations under conditions where solid-state NMR structural studies of these peptides have previously been performed.

Keywords
Transmembrane channel protein, Oriented lipid bilayer, Amphipathic α-helix, Membrane protein structure determination, Topology, Angular restraints, Tilt and rotational pitch angle, Vpu, Influenza M2
Identifiers
urn:nbn:se:umu:diva-14188 (URN)doi:10.1007/s00249-006-0122-2 (DOI)
Available from: 2007-05-24 Created: 2007-05-24 Last updated: 2018-06-09Bibliographically approved
Byström, R., Aisenbrey, C., Oliveberg, M. & Gröbner, G.Electrostatic interactions between negatively charged phospolipid membranes and SOD1 protein: Effect of charge changing fALS mutations.
Open this publication in new window or tab >>Electrostatic interactions between negatively charged phospolipid membranes and SOD1 protein: Effect of charge changing fALS mutations
(English)Manuscript (preprint) (Other (popular science, discussion, etc.))
Abstract [en]

The neurodegenerative disease amyotrophic lateral sclerosis (ALS) is closely connected to single site mutations of the Cu/Zn superoxide dismutase (SOD1) protein, whose pathological conversion into misfolded aggregates is a hallmark of ALS. To explore the impact of protein net charge changing ALS relevant SOD1 mutations on their ability to interact with neuronal membranes and the consequences for their folding behaviour, we studied by circular dichroism the conformational changes of the SOD1pWT, SOD1N86D and SOD1N86K species in their apo-state in the presence of increasing amounts of negatively charged lipid bilayers.. The results clearly indicate an electrostatically driven association process, where the association event induces a pronounced increase in the helical character of the pWT and the N86D species, characterized by long patient survival times. To the opposite, the charge reducing N86K mutation shows more pronounced β-like features in the presence of membranes in comparison to the other two species; an observation which most likely reflects its reduced stability in its apo-state in combination with a very fast ALS progression.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-26317 (URN)
Available from: 2009-10-05 Created: 2009-10-05 Last updated: 2018-06-08
Aisenbrey, C., Byström, R., Oliveberg, M. & Gröbner, G.SOD1 associates to membranes in its folded apo-state.
Open this publication in new window or tab >>SOD1 associates to membranes in its folded apo-state
(English)Manuscript (preprint) (Other (popular science, discussion, etc.))
Abstract [en]

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease accompanied by misfolding and intracellular deposition of superoxide dismutase 1 (SOD1). Although the molecular details behind this misfolding process are yet poorly understood, increasing evidence suggest that SOD1 is most susceptible to misfolding in its metal-free and relatively unstable apo-state. Here, we addressed the question, if misfolding and aggregation of SOD1 involves erroneous interactions with membranes as has been implicated for the Aβ peptide in Alzheimers disease. To examine this possibility we subjected various apo SOD1 variants to the presence of different membrane systems. The results reveal that wild type apoSOD1 but to less extent destabilized ALS mutations interact with charged vesicles under physiologically relevant conditions, thereby acquiring pronounced helical structural features. As the data further show, the protein binds to the membranes by an electrostatically driven mechanism, which requires a folded apo-state conformation and a negative membrane surface potential. Unfolded SOD1 molecules show no appreciable affinity to the membrane surfaces yielding a correlation between increased stability, i. e. occupancy of folded molecules and extend of membrane association. Since this trend opposes the correlation between decreased SOD1 stability and progression of neural damage, the results suggest that membrane association is not part of the ALS mechanism. An explanation could be that the observed membrane association of apo SOD1 is reversible and does not ‘bleed out’ in irreversible aggregation as observed for other precursors of protein-misfolding diseases.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-26314 (URN)
Available from: 2009-10-05 Created: 2009-10-05 Last updated: 2018-06-08Bibliographically approved
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