GSK3β phosphorylation catalyzes the aggregation of tau into Alzheimer's disease-like filaments.

The pathological deposition of proteins is a hallmark of several devastating neurodegenerative diseases. These pathological deposits comprise aggregates of proteins that adopt distinct structures named strains. However, the molecular factors responsible for the formation of distinct aggregate strains are unknown.

Comprehensive analysis of relaxation decays from high-resolution relaxometry.

Relaxometry consists in measuring relaxation rates over orders of magnitude of magnetic fields to probe motions of complex systems. High-resolution relaxometry (HRR) experiments can be performed on conventional high-field NMR magnets equipped with a sample shuttle. During the experiment, the sample shuttle transfers the sample between the high-field magnetic center and a chosen position in the stray field for relaxation during a variable delay, thus using the stray field as a variable field.

Explicit Models of Motion to Understand Protein Side-Chain Dynamics.

Nuclear magnetic relaxation is widely used to probe protein dynamics. For decades, most analyses of relaxation in proteins have relied successfully on the model-free approach, forgoing mechanistic descriptions of motion. Model-free types of correlation functions cannot describe a large carbon-13 relaxation dataset in protein side chains.

Convergent views on disordered protein dynamics from NMR and computational approaches.

Intrinsically disordered proteins (IDPs) or intrinsically disordered regions (IDRs) is a class of biologically important proteins exhibiting specific biophysical characteristics. They lack a hydrophobic core, and their conformational behavior is strongly influenced by electrostatic interactions. IDPs and IDRs are highly dynamic, and a characterization of the motions of IDPs and IDRs is essential for their physically correct description.

Contributions of the N-terminal intrinsically disordered region of the severe acute respiratory syndrome coronavirus 2 nucleocapsid protein to RNA-induced phase separation.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid protein is an essential structural component of mature virions, encapsulating the genomic RNA and modulating RNA transcription and replication. Several of its activities might be associated with the protein's ability to undergo liquid-liquid phase separation. N contains an intrinsically disordered region at its N-terminus (NTE) that can be phosphorylated and is affected by mutations found in human COVID-19 infections, including in the Omicron variant of concern.

Surprising absence of strong homonuclear coupling at low magnetic field explored by two-field nuclear magnetic resonance spectroscopy.

Strong coupling of nuclear spins, which is achieved when their scalar coupling is greater than or comparable to the difference in their Larmor precession frequencies in an external magnetic field, gives rise to efficient coherent longitudinal polarization transfer. The strong coupling regime can be achieved when the external magnetic field is sufficiently low, as is reduced proportional to the field strength. In the present work, however, we demonstrate that in heteronuclear spin systems these simple arguments may not hold, since heteronuclear spin-spin interactions alter the value.

Boosting the resolution of low-field [Formula: see text] relaxation experiments on intrinsically disordered proteins with triple-resonance NMR.

Improving our understanding of nanosecond motions in disordered proteins requires the enhanced sampling of the spectral density function obtained from relaxation at low magnetic fields. High-resolution relaxometry and two-field NMR measurements of relaxation have, so far, only been based on the recording of one- or two-dimensional spectra, which provide insufficient resolution for challenging disordered proteins. Here, we introduce a 3D-HNCO-based two-field NMR experiment for measurements of protein backbone [Formula: see text] amide longitudinal relaxation rates.

Quantitative Conformational Analysis of Functionally Important Electrostatic Interactions in the Intrinsically Disordered Region of Delta Subunit of Bacterial RNA Polymerase.

Electrostatic interactions play important roles in the functional mechanisms exploited by intrinsically disordered proteins (IDPs). The atomic resolution description of long-range and local structural propensities that can both be crucial for the function of highly charged IDPs presents significant experimental challenges. Here, we investigate the conformational behavior of the δ subunit of RNA polymerase from whose unfolded domain is highly charged, with 7 positively charged amino acids followed by 51 acidic amino acids.

Functionally specific binding regions of microtubule-associated protein 2c exhibit distinct conformations and dynamics.

Microtubule-associated protein 2c (MAP2c) is a 49-kDa intrinsically disordered protein regulating the dynamics of microtubules in developing neurons. MAP2c differs from its sequence homologue Tau in the pattern and kinetics of phosphorylation by cAMP-dependent protein kinase (PKA). Moreover, the mechanisms through which MAP2c interacts with its binding partners and the conformational changes and dynamics associated with these interactions remain unclear.

Protein environment affects the water-tryptophan binding mode. MD, QM/MM, and NMR studies of engrailed homeodomain mutants.

Water molecules can interact with aromatic moieties using either their O-H bonds or their lone-pairs of electrons. In proteins, water-π interactions have been reported to occur with tryptophan and histidine residues, and dynamic exchange between O-Hπ hydrogen bonding and lone-pairπ interactions was suggested to take place, based on ab initio calculations. Here we used classical and QM/MM molecular dynamics simulations, complemented with an NMR study, to examine a specific water-indole interaction observed in the engrailed homeodomain and in its mutants.

Conformational dynamics are a key factor in signaling mediated by the receiver domain of a sensor histidine kinase from .

Multistep phosphorelay (MSP) cascades mediate responses to a wide spectrum of stimuli, including plant hormonal signaling, but several aspects of MSP await elucidation. Here, we provide first insight into the key step of MSP-mediated phosphotransfer in a eukaryotic system, the phosphorylation of the receiver domain of the histidine kinase CYTOKININ-INDEPENDENT 1 (CKI1) from We observed that the crystal structures of free, Mg-bound, and beryllofluoridated CKI1 (a stable analogue of the labile phosphorylated form) were identical and similar to the active state of receiver domains of bacterial response regulators. However, the three CKI1 variants exhibited different conformational dynamics in solution.

Solution structure of domain 1.1 of the σ factor from is preformed for binding to the RNA polymerase core.

Bacterial RNA polymerase (RNAP) requires σ factors to recognize promoter sequences. Domain 1.1 of primary σ factors (σ1.

Quantitative mapping of microtubule-associated protein 2c (MAP2c) phosphorylation and regulatory protein 14-3-3ζ-binding sites reveals key differences between MAP2c and its homolog Tau.

Microtubule-associated protein 2c (MAP2c) is involved in neuronal development and is less characterized than its homolog Tau, which has various roles in neurodegeneration. Using NMR methods providing single-residue resolution and quantitative comparison, we investigated molecular interactions important for the regulatory roles of MAP2c in microtubule dynamics. We found that MAP2c and Tau significantly differ in the position and kinetics of sites that are phosphorylated by cAMP-dependent protein kinase (PKA), even in highly homologous regions.

Conformational dynamics and antigenicity in the disordered malaria antigen merozoite surface protein 2.

Merozoite surface protein 2 (MSP2) of Plasmodium falciparum is an abundant, intrinsically disordered protein that is GPI-anchored to the surface of the invasive blood stage of the malaria parasite. Recombinant MSP2 has been trialled as a component of a malaria vaccine, and is one of several disordered proteins that are candidates for inclusion in vaccines for malaria and other diseases. Nonetheless, little is known about the implications of protein disorder for the development of an effective antibody response.