The challenges of the SYNERGY endeavor require competences in pharmaceutical sciences, structural biology, lipid membrane physics, biophysics, biochemistry, spectroscopy, cell and cancer biology and signaling. The core group, consisting of Profs. Birthe B. Kragelund (main applicant), Lise Arleth, Stine F. Pedersen and Assoc. Prof. Bente Vestergaard, jointly cover these, and bring together three departments at the University of Copenhagen (UCPH).
BIRTHE B. KRAGELUND (personal homepage, ORCID ID 0000-0002-7454-1761) is professor in biostructural NMR at the Department of Biology, UCPH. From a background in protein NMR spectroscopy, Birthe has successfully pushed the quest for understanding the impact of protein disorder and functional dynamics on biology, propagating knowledge to the scientific community also outside the field of structural biology, and pioneering the characterization of intrinsically disordered proteins (IDPs) in particular in membrane proteins. Birthe's research addresses protein ID at several levels, and includes the associated fields of protein folding and protein interactions. BBK has a broad collaborative network ranging from ecology, biology, chemistry, cell-biology, physics to biochemistry, all documented in her records, and she heads such studies as well as stimulate their developments. All of this testifies to her ability to promote scientific ideas, reach other fields and establish collaborations broadly. She has a proven track record of theoretical, practical and strategic research and human resource management. Since 2011 Birthe has headed the Structural Biology and NMR Lab. with 3 research groups (>40 pers). She is appointed member of the BIO Strategic Res. Com., of the Villum found. young investigator board, has pioneered the turnaround of the Biochemistry study program (2013), and is a Faculty study board member. These diverse involvements demonstrate her initiative, capacity and leadership.
STINE FALSIG PEDERSEN (personal homepage, ORCID ID 0000-0002-3044-7714) is professor in cell biology at the Department of Biology, UCPH, with extensive expertise in studying regulation and function of membrane transport proteins, with particular emphasis on acid-base transporters including ssodium protein exchanger 1 (NHE1). She has published extensively on NHE1 structure:function, regulation and dysregulation in disease, and her group is internationally recognized for their work on acid-base transport in cancer. Unpublished results with Birthe B. Kragelund reveal NHE1 intracellular domain interactions with multiple lipids, in a manner dependent on pH and ancillary proteins. Experimentally, expertise includes real-time imaging of pH in live cells, cellular signaling, complex cell culture systems, and a broad range of molecular and cell biological techniques.
LISE ARLETH (personal homepage, ORCID ID 0000-0002-4694-4299) is professor in Experimental Biophysics at the Niels Bohr Institute, UCPH. Lise is an international expert in Small-Angle X-ray and Neutron Scattering (SAXS and SANS) applied to various biological structures. Her group (6 PhD’s and Post Docs) maintains state of the art expertise within SAXS/SANS sample preparation, experiments and advanced data analysis. Lise’s present research is focused on developing approaches for obtaining direct structural and dynamical information about membrane proteins under solution conditions. This work relies on the ApoA1-derived nanodisc system, which is used as a particularly well-defined molecular sample holder for membrane proteins enabling investigations of the structure of both membrane protein and the embedding bilayer membrane and on neutron contrast optimised carrier systems. Unpublished work from Lise shows that well-defined samples of tissue factor (TF) reconstituted in nanodiscs can be obtained and that TF/factor VIIa (FVIIa) complex is stabilized in phosphatidyl serine containing-nanodiscs.
BENTE VESTERGAARD (personal homepage, ORCID ID 0000-0001-8011-6414) is assoc. professor at PHARMA, UCPH and has a background in protein crystallography and combined cryo-EM and high-resolution analysis. In 2007, she founded the first Scandinavian BioSAXS group, focusing on extensive structural solution characterization of complex, dynamic systems of relevance in pharmaceutical sciences. The group has a particular focus on amyloid fibrillation, and BV has pioneered the use of SAXS as a tool to structurally describe accumulating amyloid oligomers while they co-exist with amyloid fibrils. In recent work, we demonstrate the molecular principles behind α-synucleain (αSN) fibril elongation. Importantly, we have shown that specific αSN amyloid oligomers disrupt model lipid bilayers and protein:lipid soluble co-aggregates are formed. Unpublished results reveal how amyloid aggregates alter the lipid bilayer alternatively depending on the lipid composition and how membrane vicinity alters the αSN folding landscape and results in alternative protein aggregate pathways (di Carlo et al in review). We investigated the altered structural dynamcis of αSN dimers generated by oxidative stress, and reveal how these alter the fibrillation kinetics. In total, the research focus over recent years demonstrates how the 3D structural landscape of several protein systems and amyloid proteins in particular is much more complex than normally anticipated. It is shown how the experimental context, including the lipid environment, alters the structural preferences of proteins and thereby links to protein mis-folding diseases and amyloid toxicity.