A5000943271- Protein Structure and Dynamics
- Enzyme Structure and Function
- ATP Synthase and ATPases Research
- Ion Transport and Channel Regulation
- Cellular transport and secretion
- RNA and protein synthesis mechanisms
- Alzheimer's disease research and treatments
- Protein Kinase Regulation and GTPase Signaling
- Protease and Inhibitor Mechanisms
- Photosynthetic Processes and Mechanisms
- Microtubule and mitosis dynamics
- Computational Drug Discovery Methods
- Advanced Fluorescence Microscopy Techniques
- Mass Spectrometry Techniques and Applications
- Molecular spectroscopy and chirality
- Prion Diseases and Protein Misfolding
- Enzyme Production and Characterization
- Fungal and yeast genetics research
- Blood Coagulation and Thrombosis Mechanisms
- Ion channel regulation and function
- Lipid Membrane Structure and Behavior
- RNA Research and Splicing
- Protein purification and stability
- Glycosylation and Glycoproteins Research
- Trace Elements in Health
Aarhus University
2016-2025
Danish National Research Foundation
2016-2025
Foundation Center
2020-2024
Danish Pain Research Center
2024
Danish Diabetes Academy
2019-2020
Instituto de Estudos Avançados da Universidade de São Paulo
2019-2020
Promundo
2019
University of Cambridge
2013-2018
University of Copenhagen
2007-2014
University of California, San Diego
2006-2010
Abstract Protein aggregation plays a key role in neurodegenerative disease, giving rise to small oligomers that may become cytotoxic cells. The fundamental microscopic reactions taking place during aggregation, and their rate constants, have been difficult determine due lack of suitable methods identify follow the low concentration over time. Here we use single-molecule fluorescence study repeat domain tau (K18), two mutant forms linked with familial frontotemporal dementia, deletion ΔK280...
Structural characterization of intrinsically disordered proteins (IDPs) is mandatory for deciphering their potential unique physical and biological properties. A large number circular dichroism (CD) studies have demonstrated that a structural change takes place in IDPs with increasing temperature, which most likely reflects formation transient alpha-helices or loss polyproline II (PPII) content. Using three IDPs, ACTR, NHE1, Spd1, we show the temperature-induced common among accompanied by...
Native molten globules are the most folded kind of intrinsically disordered proteins. Little is known about mechanism by which native bind to their cognate ligands form fully complexes. The nuclear coactivator binding domain (NCBD) CREB protein particularly interesting in this respect as structural studies its complexes have shown that NCBD folds into two remarkably different states depending on ligand being ACTR or IRF-3. ligand-free state was characterized order understand folding upon...
Abstract Many intrinsically disordered proteins fold upon binding to other macromolecules. The secondary structure present in the well‐ordered complex is often formed transiently unbound state. consequence of such transient for process is, however, not clear. activation domain activator thyroid hormone and retinoid receptors (ACTR) folds nuclear coactivator (NCBD) CREB protein. A number mutants was designed that selectively perturbs amount ACTR without interfering with intermolecular...
Many multidomain proteins contain disordered linkers that regulate interdomain contacts, and thus the effective concentrations govern intramolecular reactions. Effective are rarely measured experimentally, therefore little is known about how they relate to linker architecture. We have directly enforced by protein using a fluorescent biosensor. show follow simple geometric models based on polymer physics, offering an indirect method probe structural properties of linker. The compaction...
As a key player of the protein quality control network cell, molecular chaperone Hsp70 inhibits aggregation amyloid tau. To date, mechanism this inhibition and tau species targeted by remain unknown. This is partly due to inherent difficulty studying aggregates because their heterogeneous transient nature. Here, we used ensemble single-molecule fluorescence measurements dissect how counteracts self-assembly process K18 ΔK280 variant. We found that blocks early stages suppressing formation...
The misfolding and aggregation of proteins into amyloid fibrils characterizes many neurodegenerative disorders such as Parkinson's Alzheimer's diseases. We report here a method, termed SAVE (single aggregate visualization by enhancement) imaging, for the ultrasensitive detection individual oligomers using single-molecule fluorescence microscopy. demonstrate that this method is able to detect presence aggregates α-synuclein, tau, amyloid-β. In addition, we show can also be identified in human...
A general non-binary definition for on- and off-pathway intermediates is developed, enabling comparison of amyloid oligomers' contributions to fibril formation.
The molecular mechanism of protein aggregation is both fundamental and clinical importance as amyloid aggregates are linked to a number neurodegenerative disorders. Such include macroscopic insoluble fibrils well small soluble oligomeric species. Time-dependent resolution these species prerequisite for detailed quantitative understanding aggregation; this remains challenging due the lack methods detecting characterizing transient heterogeneous oligomers. Here we have used single molecule...
Significance Kinases are often tethered to their substrates, and many phosphorylation reactions thus occur inside macromolecular complexes. However, it is currently not known how such tethering affects the rate of phosphorylation. We show that can enhance by orders magnitude but enhancement highly sensitive length linker. provide an equation describing rates only partially be predicted from untethered reactions. suggest a mechanism for changes in linkers scaffolding proteins may alter output...
Many kinases use reversible docking interactions to augment the specificity of their catalytic domains. Such are often structurally independent domain, which allow for a flexible combination modules in evolution and bioengineering. The affinity spans several orders magnitude. This led us ask how interaction affects enzymatic activity pick optimal module complement given substrate. Here, we develop equations that predict binding strength kinase validate it using numerical simulations...
Abstract Many proteins do not fold into a fixed three-dimensional structure, but rather function in highly disordered state. These intrinsically pose unique challenge to protein engineering and design: How can be designed de novo if by tailoring their structure? Here, we will review the nascent field of design with focus on applications biotechnology medicine. The goals should necessarily same as for folded have functional strengths limitations. We functions where are uniquely suited...
Abstract Active transport by P-type Ca 2+ -ATPases maintain internal calcium stores and a low cytosolic concentration. Structural studies of mammalian sarco/endoplasmic reticulum (SERCA) have revealed several steps the cycle, but calcium-releasing intermediate has remained elusive. Single-molecule FRET bacterial -ATPase LMCA1 an transition between so-called [Ca]E1P E2P states suggested that release from this was essentially irreversible step transport. Here, we present 3.5 Å resolution...
Intrinsically disordered proteins such as amyloid-β (Aβ), prion protein (PRP) and α-synuclein bind copper-ions through histidine-rich motifs. Several of these copper-binding motifs catalyze formation reactive oxygen species (ROS), which is believed to be involved in proteins' role neurodegenerative disorders. The catalytic mechanism rely on binding an "in-between state", energetically available both Cu(I) Cu(II) thus allow redox cycling. Presently, our knowledge ROS generation based a few...
The urokinase-type plasminogen activator receptor (uPAR or CD87) is a glycolipid-anchored membrane glycoprotein, which responsible for focalizing activation to the cell surface through its high-affinity binding serine protease uPA. This tight interaction (KD less than 1 nM) accomplished by an unusually large and hydrophobic cavity in uPAR that created unique interdomain assembly involving all three homologous domains of receptor. These belong Ly-6/uPAR (LU) protein domain family, defined...
Intrinsic disorder is important for protein regulation, yet its role in regulation of ion transport proteins essentially uninvestigated. The ubiquitous plasma membrane carrier Na(+)/H(+) Exchanger isoform 1 (NHE1) plays pivotal roles cellular pH and volume homeostasis, dysfunction implicated several clinically diseases. This study shows, the first time any protein, that distal part C-terminal intracellular tail (the cdt, residues V686-Q815) from human (h) NHE1 intrinsically disordered....