Lipids as catalysts of protein misfolding
For a fairly recent invited lecture, please see this youtube video.
The unit of life is the cell. Its outer border is the cell membrane, a thin sheet just a few nanometers thick. This is not a solid barrier, but rather a semi-fluid oil-like affair. It consists of lipids, molecules similar to fats or oils and proteins. There are also chains of sugar molecules linked to it. The cell membrane allows some molecules to pass through it, but is impassable to others. Many of both the protein, lipid and sugar molecules of the cell membrane are well-understood in terms individual behavior. But in the complex and constantly changing environment of the membrane it has remained a challenge to understand how each component may affect each other. And understanding this interplay is critical for understanding the molecular foundation of the cell. This project intends to examine how lipids affect proteins and how proteins affect the integrity of the lipid assembly that gives the cell membrane its integrity as a barrier. One of the main questions asked is whether some lipids or states of the membrane can cause certain proteins to misform. Proteins normally need to twist their shape into a specific structure, or fold, to gain their function. If this process, which is usually spontaneous, is disturbed, they can form damaging states instead. This is normally referred to as protein misfolding, and we asks whether some lipids can prompt certain membrane-associated proteins to misfold at a quicker pace than they normally would. Such misfolding events are implicated in many diseases, including Parkinson's, Alzheimer's and Diabetes II, as well as prionic diseases. If the scientific question is well posed and the project manages to pursue it with appropriate techniques it is possible that one might gain new and detailed insight into disease mechanisms. This could in time lead to better prevention or treatments. Our preliminary findings indicate that cells modulate their lipid composition to a large extent throughout their life-time. The lipid mixes are so different that that the physical properties of the membrane changes significantly. We also find that different lipid mixes affect the aggregation-rates of model peptide systems.
We aim to use zebrafish as model organism to conduct neurolipidomics related to ageing and (models) of neurodegenerative diseases. Using biophysics and structural biology, we will investigate whether certain lipids and membrane associated proteins, in particular phosphoinositides and so-called scaffold proteins , act as moderators of misfolding. The biophysics and structural biology of this is being investigated, with a focus on “invisible protein states”, i.e., states that are not detectable by normal means. We also wish to know where in a cell misfolded protein accumulates, and whether this localization can be linked to lipid metabolism, thereby establishing a link between misfolding and lipidome. We will introduce of misfolders (in functional, misfolded and inert states) into cells to discover subcellular locations affected by misfolding, with a particular attention to functional assemblies of lipases, cholesterol and phosphoinesotides.
MBV 9520 (2x45 min lecture in protein dynamics, national-level Biostruct-course)
MOL950 (a practical NMR module, national-level Biostruct-course)
Lecture in BMED325 - Nanobiochemistry
Lecture in Atomic Force Microscopy (national-level Biostruct-course)
Guest lectures and leading discussions in BMED310 - Philosophy of Science
Statistics (SOK33B) and Inorganic chemistry
Here is my academic production in:
Below is also my CRIStin publication list.
- (2022). How Honey Bee Vitellogenin Holds Lipid Cargo: A Role for the C-Terminal. Frontiers in Molecular Biosciences. 8 pages.
- (2022). Binding Specificity of ASHH2 CW Domain Toward H3K4me1 Ligand Is Coupled to Its Structural Stability Through Its α1-Helix. Frontiers in Molecular Biosciences. 1-16.
- (2021). The biosynthesis of phospholipids is linked to the cell cycle in a model eukaryote . Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids.
- (2021). Structure prediction of honey bee vitellogenin: a multi-domain protein important for insect immunity. FEBS Open Bio. 51-70.
- (2021). Investigating the Disordered and Membrane-Active Peptide A-Cage-C Using Conformational Ensembles. Molecules. 3607.
- (2020). The Attenuating Effects of 14-3-3eta in Parkinson’s Disease-Related alpha-Synuclein Aggregation.
- (2020). The Arabidopsis (ASHH2) CW domain binds monomethylated K4 of the histone H3 tail through conformational selection. The FEBS Journal. 4458-4480.
- (2020). Senescence-Related Changes to the Lipid Composition of SH-SY5Y Cells with Implications for α-Synuclein Misfolding.
- (2020). Plasma-derived exosome-like vesicles are enriched in lyso-phospholipids and pass the blood-brain barrier. PLOS ONE. 1-15.
- (2020). Phosphorylated TH hinges with vesicular membrane proteins for axonal transport.
- (2020). Lipiders rolle i nevrodegenerative sykdommer. NBS-nytt.
- (2020). Conformational selection in histone binding – when being rigid fails.
- (2020). Cholesterol-containing lipid nanodiscs promote an α-synuclein binding mode that accelerates oligomerization. The FEBS Journal.
- (2020). Bioactive metabolites of marine origin have unusual effects on model membrane systems. Marine Drugs. 1-11.
- (2019). Neuronal cell lipidomics and role of cholesterol in α-synuclein binding and aggregation.
- (2019). Neurodegenerative sykdommer -- proteinkrøll gir hjernekrøll.
- (2019). Misfolding i neurodegenerative sykdommer.
- (2019). From potent toxin to vaccine toxoid: Engineering the enterotoxigenic Escherichia coli heat-stable toxin into a subunit vaccine component.
- (2019). Fast and quantitative phospholipidomic analysis of SH-SY5Y neuroblastoma cell cultures using LC-MS/MS and 31P NMR. ACS Omega. 21596-21603.
- (2018). Proteiner og nevrodegenerative sykdommer.
- (2018). Contrasting cellular lipid states using quantitative 31P NMR and LC MS/MS .
- (2018). CW-domain of ASHH2 methyltransferase: structural basis of ligand binding and specificity.
- (2018). Alpha-synuclein oligomerization in the presence of the cholesterol and glycerophosphoglycerol.
- (2018). A novel exosome-like nanocarrier for treatment of refractory epilepsy .
- (2018). A novel exosome-like nanocarrier for treatment of refractory epilepsy .
- (2018). A novel exosome-like nanocarrier for treatment of refractory epilepsy .
- (2018). A biophysical study on the mechanism of interactions of DOX or PTX with α-lactalbumin as a delivery carrier. Scientific Reports. 1-21.
- (2018). 1H, 13C, and 15N resonance assignments of CW domain of the N-methyltransferase ASHH2 free and bound to the mono-, di- and tri-methylated histone H3 tail peptides. Biomolecular NMR Assignments. 215-220.
- (2017). Spectroscopic and AFM characterization of polypeptide-surface interactions: Controls and lipid quantitative analyses. Data in Brief. 113-122.
- (2017). Peptides derived from α-lactalbumin membrane binding helices oligomerize in presence of lipids and disrupt bilayers. Biochimica et Biophysica Acta - Biomembranes. 1029-1039.
- (2017). Lecture on the Nobel Prize of Chemistry 2017 (Cryo-EM).
- (2017). Evidence that Listeria innocua modulates its membrane's stored curvature elastic stress, but not fluidity, through the cell cycle. Scientific Reports. 1-11.
- (2017). Does the lipid fractio of Listeria innocua change as a function of the cell cycle?
- (2016). Why is HAMLET more toxic to dividing cells?
- (2016). The protein, fatty acid and lipid components in early stages of PFA/HAMLET-induced cell death.
- (2016). Reversible protein membrane interactions by mobile peptides.
- (2016). Relevance of the protein, fatty acid and lipid component in early stages of HAMLET induced cell death.
- (2016). Molecular Characteristics of Peptide-Fatty Acid Complex Relevant for Tumoricidal HAMLET.
- (2016). Expression and purification of misfolding peptides from E. coli for spectroscopic characterization.
- (2016). Detection of misfolded protein aggregates from a clinical perspective. Journal of Clinical and Translational Research. 11-26.
- (2016). Detection of Misfolded Protein Aggregates from a Clinical Perspective. Journal of Clinical and Translational Research. 11-26.
- (2016). Characterization of protein-fatty acid complexe.
- (2015). α-lactalbumin: oleic acid complex spontaneously delivers oleic acid to artificial and erythrocyte membranes. Journal of Molecular Biology (JMB). 3177-3187.
- (2014). Two homologous neutrophil serine proteases bind to POPC vesicles with different affinities: When aromatic amino acids matter. Biochimica et Biophysica Acta - Biomembranes. 3191-3202.
- (2014). The N-terminal sequence of tyrosine hydroxylase is a conformationally versatile motif that binds 14-3-3 proteins and membranes. Journal of Molecular Biology (JMB). 150-168.
- (2013). Vitellogenin recognizes cell damage through membrane binding and shields living cells from reactive oxygen species. Journal of Biological Chemistry. 28369-28381.
- (2013). Tunable photophysical properties, conformation and function of nanosized protein–gold constructs. RSC Advances. 482-495.
- (2013). HIV-1 p6 - a structured to flexible multifunctional membrane-interacting protein. Biochimica et Biophysica Acta - Biomembranes. 816-823.
- (2013). Cytotoxicity of bovine alpha-lactalbumin: Oleic acid complexes correlates with the disruption of lipid membranes. Biochimica et Biophysica Acta - Biomembranes. 2691-2699.
- (2013). CREATING BAMLET USING ALPs AND INVESTIGATING THEIR EFFECT ON DIFFERENTIATED AND NONDIFFERENTIATED HUMAN BREAST CANCER CELLS.
- (2013). Anticancer Activity from Gold-alpha-Lactalbumin Nanoconstructs? Journal of Physical Chemistry C. 2230-2238.
- (2012). The peripheral binding of 14-3-3gamma to membranes involves isoform-specific histidine residues. PLOS ONE.
- (2012). PR3 Interacts Directly to Lipid Bilayers: Evidence from MD Simulations and SPR Experiments.
- (2012). PR3 Interacts Directly to Lipid Bilayers: Evidence from MD Simulations and SPR Experiments. Biophysical Journal. 497A-497A.
- (2012). Interactions between BSA-gold nanoparticle constructs and a phospholipid monolayer.
- (2012). HAMLET forms annular oligomers when deposited with phoshpolipid monolayers. Journal of Molecular Biology (JMB). 90-102.
- (2012). Generally applicable procedure for in situ formation of fluorescent protein-gold nanoconstructs. RSC Advances. 11704-11711.
- (2012). An x-linked infantile lethal disorder caused by N-terminal acetyltransferase deficiency.
- (2012). A vitellogenin polyserine cleavage site: highly disordered conformation protected from proteolysis by phosphorylation. Journal of Experimental Biology. 1837-1846.
- (2011). The binding of 14-3-3 gamma to membranes studied by intrinsic fluorescence spectroscopy. FEBS Letters. 1163-1168.
- (2011). Teaching old proteins new tricks.
- (2011). Social pleiotropy and evolution of honey bee vitellogenin. Molecular Ecology. 5111-5113.
- (2011). Mechanism for tunable protein deposition onto charged monodisperse polymer nanoparticles.
- (2011). Interactions of α-Lactalbumin and Cytochrome с with Langmuir Monolayers of Glycerophospholipids. Journal of Dispersion Science and Technology. 150-158.
- (2011). Immobilizaton onto gold nanoparticles alters α-lactalbumin interaction with pure and mixed phospholipid monolayers. Soft Matter. 11501-11509.
- (2011). Emergent membrane-affecting properties of BSA-gold nanoparticle constructs. Nanoscale. 1788-1797.
- (2011). Deconstructing honeybee vitellogenin: novel 40 kDa fragment assigned to its N terminus. Journal of Experimental Biology. 582-592.
- (2011). Benchmarking Different BAMLET-like Preparations with Resepct to Tryptophan Exposure, Interfacial Activity, and Effect on Cell Viability. Bioanalysis & Biomedicine. 5 pages.
- (2010). HAMLET interacts with lipid membranes and perturbs their structure and integrity. PLOS ONE. 10 pages.
- (2010). Adsorption and bioactivity of tyrosine hydroxylase on gold surfaces and nanoparticles. Protein & Peptide Letters. 1376-1382.
- (2009). Three-way interaction between 14-3-3 proteins, the N-terminal region of tyrosine hydroxylase and negatively charged membranes. Journal of Biological Chemistry. 32758-32769.
- (2009). Same System-Different Results: The Importance of Protein. Introduction Protocols in Langmuir-Monolayer Studies of Lipid-Protein Interactions. Analytical Chemistry. 3042-3050.
- (2009). Linking new paradigms in protein chemistry to reversible membrane-protein interactions. Current Protein & Peptide Science. 339-359.
- (2009). Exploring the Membrane Binding Capacity and Mechanism of 14-3-3γ.
- (2009). Amino acid contacts in proteins adapted to different temperatures: hydrophobic interactions and surface charges play a key role. Extremophiles. 11-20.
- (2008). Large-scale modulation of thermodynamic protein folding barriers linked to electrostatics. Proceedings of the National Academy of Sciences of the United States of America. 8625-8630.
- (2008). Amino acid contacts in proteins adapted to different temperatures: hydrophobic interactions and surface charges play a key role. Extremophiles.
- (2007). Structure-dependent relationships between growth temperature of prokaryotes and the amino acid frequency in their proteins. Extremophiles. 585-596.
- (2007). Adsorption Behavior of Acidic and Basic Proteins onto Citrate-Coated Au Surfaces Correlated to Their Native Fold, Stability, and pI. Journal of Physical Chemistry B.
- (2005). α-Lactalbumin binding and membrane integrity – effect of charge and degree of unsaturation of glycerophospholipids. Biochimica et Biophysica Acta - Biomembranes. 11-20.
- (2005). alpha-Lactalbumin binding and membrane integrity--effect of charge and degree of unsaturation of glycerophospholipids. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. 11-20.
- (2005). Structure and dynamics of the peripheral protein Lactalbumin in relation to its membrane binding capability.
- (2005). Conformational flexibility of alpha-lactalbumin related to its membrane binding capacity. Journal of Molecular Biology (JMB). 1072-1086.
- (2003). The interaction of peripheral proteins and membranes studied with alpha-lactalbumin and phospholipid bilayers of various compositions. Journal of Biological Chemistry. 21790-21797.
- (2003). Direct and indirect NMR techniques applied on alpha-lactalbumin bound to different membrane-mimicking systems.
- (2002). The membrane bound conformation of alpha-lactalbumin studied by NMR.
- (2002). The Membrane-bound Conformation of a-Lactalbumin Studied by NMR-monitored 1H Exchange. Journal of Molecular Biology (JMB). 99-110.
- (2002). Studying the interaction between 14-3-3 proteins and tryptophan hydroxylase using 3D-modelling and NMR spectroscopy.
- (2002). Molten globule state of BLA bound to SDS micelles studied by NMR spectroscopy.
- (2002). Elucidating the membrane bound conformations of -lactalbumin in different lipid environments by CD, multidimensional NMR spectroscopy and fluorescence.
- (2002). Detaljer i utilgjengelig systemer membran-protein vekselvirkninger. NBS-nytt. 16-19.
- (2000). The membrane bound conformation of bovine alpha-lactalbumin studied by NMR-monitored 1H-exchange.
- (2000). Conformation of alpha-lactalbumin bound to model membranes studied by NMR-monitored hydrogen exchange.
2014:The membrane as a catalyst of damaging protein misfolding events (Research Council of Norway grant #240063)
2009: Interfaces as folding templates for polypetides (With associate professor Wilhelm Glomm)
2008: From details to drugs – a thorough structural and dynamic analysis of 14-3-3, tyrosine hydroxylase and membranes (Lie and Jensens fund/Norwegian Cancer Society, grant #58240001, with Professor Aurora Martínez)
2007: Dissecting molecular properties of honey bee vitellogenin (Research Council of Norway, grant #185306, with Professor Gro Vang Amdam)
2006: Linking new paradigms in protein chemistry to membrane-protein interaction, apoptosis and signalling (Norwegian Cancer Society, grant #06109/01, with Professor Aurora Martínez)
2002: Structural characterization of protein folding variants that induce apoptosis in tumor cells (Research Council of Norway, grant #149117, with Professor Aurora Martínez)
Sara Torvholm Frøystad, Master Student 2022-2023 (co-supervised with Aurelia Lewis and Diana Turcu)
Luisa Botnen van den Bergh, Master Student 2021-2022 (co-supervised with Aurelia Lewis and Diana Turcu)
Kristoffer Prince, Master Student 2021-2022 (co-supervised with Jarl Underhaug and Diana Turcu)
Vilde Leipart, PhD Student 2018-2022 (co-supervised with Gro Amdam)
Martin Jakubec, PhD Student 2015-2018
Maxim Bril'kov, PhD Student 2014-2018
Espen Bariås, PhD Student 2017-2021
Morten Andreas Govasli Larsen, PhD Student 2015-2018 (co-supervised with Pål Puntervoll)
Vinnit Georg, Master Student 2017-2018 (co-supervised with Jarl Underhaug)
Samuel Furse, Post Doc, 2015-2017
Lene Reed Hjorteset, Master Student 2015-2016
Øyvind Strømland, PhD Student 2012-2016
Hanzhen Wen, PhD Student 2010-2014
Ørjan Handegård, Master Student 2015-2016
Christophe Louis Balin, Master Student 2015-2016
Øyvind Ødegård, Master Student 2014-2015
Morten Andreas Govasli Larsen, Master Student 2013-2014
Helene Sandnes, Master Student 2012-2013
Ida Marie Lundgren, Master Student 2010-2011
Vinnit Georg (2017), Ørjan Handegård (2015), Nhi Nguyen (2011), Katharina Leopold (2011)