Tau seed amplification assay reveals relationship between seeding and pathological forms of tau in Alzheimer's disease brain.

Tau seed amplification assays (SAAs) directly measure the seeding activity of tau and would therefore be ideal biomarkers for clinical trials targeting seeding-competent tau in Alzheimer's disease (AD). However, the precise relationship between tau seeding measured by SAA and the levels of pathological forms of tau in the AD brain remains unknown. We developed a new tau SAA based on full-length 0N3R tau with sensitivity in the low fg/ml range and used it to characterize 103 brain samples from three independent cohorts.

Structure and physiological function of the human KCNQ1 channel voltage sensor intermediate state.

Voltage-gated ion channels feature voltage sensor domains (VSDs) that exist in three distinct conformations during activation: resting, intermediate, and activated. Experimental determination of the structure of a potassium channel VSD in the intermediate state has previously proven elusive. Here, we report and validate the experimental three-dimensional structure of the human KCNQ1 voltage-gated potassium channel VSD in the intermediate state.

Alcohol and cannabis use alter pulmonary innate immunity.

Purpose: Cannabis use is increasing due to recent legislative changes. In addition, cannabis is often used in conjunction with alcohol. The airway epithelium is the first line of defense against infectious microbes.

Mechanisms of KCNQ1 channel dysfunction in long QT syndrome involving voltage sensor domain mutations.

Mutations that induce loss of function (LOF) or dysfunction of the human KCNQ1 channel are responsible for susceptibility to a life-threatening heart rhythm disorder, the congenital long QT syndrome (LQTS). Hundreds of mutations have been identified, but the molecular mechanisms responsible for impaired function are poorly understood. We investigated the impact of 51 KCNQ1 variants with mutations located within the voltage sensor domain (VSD), with an emphasis on elucidating effects on cell surface expression, protein folding, and structure.

Predicting the Functional Impact of KCNQ1 Variants of Unknown Significance.

Background: An emerging standard-of-care for long-QT syndrome uses clinical genetic testing to identify genetic variants of the KCNQ1 potassium channel. However, interpreting results from genetic testing is confounded by the presence of variants of unknown significance for which there is inadequate evidence of pathogenicity.

Methods And Results: In this study, we curated from the literature a high-quality set of 107 functionally characterized KCNQ1 variants.

Comparing the effects of adapting to a weight on one leg during treadmill and overground walking: A pilot study.

Background: Locomotor adaptation has been suggested as a way to improve gait symmetry in individuals post-stroke. Most perturbation methods utilize costly, specialized equipment. The use of a unilateral leg weight may provide a low cost, clinically translatable alternative.

The molecular architecture of the yeast spindle pole body core determined by Bayesian integrative modeling.

Microtubule-organizing centers (MTOCs) form, anchor, and stabilize the polarized network of microtubules in a cell. The central MTOC is the centrosome that duplicates during the cell cycle and assembles a bipolar spindle during mitosis to capture and segregate sister chromatids. Yet, despite their importance in cell biology, the physical structure of MTOCs is poorly understood.

Regulation of KCNQ/Kv7 family voltage-gated K channels by lipids.

Many years of studies have established that lipids can impact membrane protein structure and function through bulk membrane effects, by direct but transient annular interactions with the bilayer-exposed surface of protein transmembrane domains, and by specific binding to protein sites. Here, we focus on how phosphatidylinositol 4,5-bisphosphate (PIP) and polyunsaturated fatty acids (PUFAs) impact ion channel function and how the structural details of the interactions of these lipids with ion channels are beginning to emerge. We focus on the Kv7 (KCNQ) subfamily of voltage-gated K channels, which are regulated by both PIP and PUFAs and play a variety of important roles in human health and disease.

Structural basis for KCNE3 modulation of potassium recycling in epithelia.

The single-span membrane protein KCNE3 modulates a variety of voltage-gated ion channels in diverse biological contexts. In epithelial cells, KCNE3 regulates the function of the KCNQ1 potassium ion (K(+)) channel to enable K(+) recycling coupled to transepithelial chloride ion (Cl(-)) secretion, a physiologically critical cellular transport process in various organs and whose malfunction causes diseases, such as cystic fibrosis (CF), cholera, and pulmonary edema. Structural, computational, biochemical, and electrophysiological studies lead to an atomically explicit integrative structural model of the KCNE3-KCNQ1 complex that explains how KCNE3 induces the constitutive activation of KCNQ1 channel activity, a crucial component in K(+) recycling.

A composite approach towards a complete model of the myosin rod.

Sarcomeric myosins have the remarkable ability to form regular bipolar thick filaments that, together with actin thin filaments, constitute the fundamental contractile unit of skeletal and cardiac muscle. This has been established for over 50 years and yet a molecular model for the thick filament has not been attained. In part this is due to the lack of a detailed molecular model for the coiled-coil that constitutes the myosin rod.

Kinesin-2 KIF3AC and KIF3AB Can Drive Long-Range Transport along Microtubules.

Mammalian KIF3AC is classified as a heterotrimeric kinesin-2 that is best known for organelle transport in neurons, yet in vitro studies to characterize its single molecule behavior are lacking. The results presented show that a KIF3AC motor that includes the native helix α7 sequence for coiled-coil formation is highly processive with run lengths of ∼1.23 μm and matching those exhibited by conventional kinesin-1.

Skip residues modulate the structural properties of the myosin rod and guide thick filament assembly.

The rod of sarcomeric myosins directs thick filament assembly and is characterized by the insertion of four skip residues that introduce discontinuities in the coiled-coil heptad repeats. We report here that the regions surrounding the first three skip residues share high structural similarity despite their low sequence homology. Near each of these skip residues, the coiled-coil transitions to a nonclose-packed structure inducing local relaxation of the superhelical pitch.

Insights into the specificity of lysine acetyltransferases.

Reversible lysine acetylation by protein acetyltransferases is a conserved regulatory mechanism that controls diverse cellular pathways. Gcn5-related N-acetyltransferases (GNATs), named after their founding member, are found in all domains of life. GNATs are known for their role as histone acetyltransferases, but non-histone bacterial protein acetytransferases have been identified.

Ultrafast E to Z photoisomerization dynamics of the Cph1 phytochrome.

Femtosecond photodynamics of the reverse ( P→ P) reaction of the red/far-red phytochrome Cph1 from were resolved with visible broadband transient absorption spectroscopy. Multi-phasic dynamics were resolved and separated via global target analysis into a fast-decaying (260 fs) excited-state population that bifurcates to generate the isomerized Lumi-F primary photoproduct and a non-isomerizing vibrationally excited ground state that relaxes back into the P ground state on a 2.8-ps time scale.

Structural organization of FtsB, a transmembrane protein of the bacterial divisome.

We report the first structural analysis of an integral membrane protein of the bacterial divisome. FtsB is a single-pass membrane protein with a periplasmic coiled coil. Its heterologous association with its partner FtsL represents an essential event for the recruitment of the late components to the division site.

Ultrafast excited-state isomerization in phytochrome revealed by femtosecond stimulated Raman spectroscopy.

Photochemical interconversion between the red-absorbing (P(r)) and the far-red-absorbing (P(fr)) forms of the photosensory protein phytochrome initiates signal transduction in bacteria and higher plants. The P(r)-to-P(fr) transition commences with a rapid Z-to-E photoisomerization at the C(15)=C(16) methine bridge of the bilin prosthetic group. Here, we use femtosecond stimulated Raman spectroscopy to probe the structural changes of the phycocyanobilin chromophore within phytochrome Cph1 on the ultrafast time scale.