326 research outputs found
Phosphorylation of FEZ1 by Microtubule Affinity Regulating Kinases regulates its function in presynaptic protein trafficking
Adapters bind motor proteins to cargoes and therefore play essential roles in Kinesin-1 mediated intracellular transport. The regulatory mechanisms governing adapter functions and the spectrum of cargoes recognized by individual adapters remain poorly defined. Here, we show that cargoes transported by the Kinesin-1 adapter FEZ1 are enriched for presynaptic components and identify that specific phosphorylation of FEZ1 at its serine 58 regulatory site is mediated by microtubule affinity-regulating kinases (MARK/PAR-1). Loss of MARK/PAR-1 impairs axonal transport, with adapter and cargo abnormally co-aggregating in neuronal cell bodies and axons. Presynaptic specializations are markedly reduced and distorted in FEZ1 and MARK/PAR-1 mutants. Strikingly, abnormal co-aggregates of unphosphorylated FEZ1, Kinesin-1 and its putative cargoes are present in brains of transgenic mice modelling aspects of Alzheimer's disease, a neurodegenerative disorder exhibiting impaired axonal transport and altered MARK activity. Our findings suggest that perturbed FEZ1-mediated synaptic delivery of proteins arising from abnormal signalling potentially contributes to the process of neurodegeneration
Study of the decay
The decay is studied
in proton-proton collisions at a center-of-mass energy of TeV
using data corresponding to an integrated luminosity of 5
collected by the LHCb experiment. In the system, the
state observed at the BaBar and Belle experiments is
resolved into two narrower states, and ,
whose masses and widths are measured to be where the first uncertainties are statistical and the second
systematic. The results are consistent with a previous LHCb measurement using a
prompt sample. Evidence of a new
state is found with a local significance of , whose mass and width
are measured to be and , respectively. In addition, evidence of a new decay mode
is found with a significance of
. The relative branching fraction of with respect to the
decay is measured to be , where the first
uncertainty is statistical, the second systematic and the third originates from
the branching fractions of charm hadron decays.Comment: All figures and tables, along with any supplementary material and
additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-028.html (LHCb
public pages
Measurement of the ratios of branching fractions and
The ratios of branching fractions
and are measured, assuming isospin symmetry, using a
sample of proton-proton collision data corresponding to 3.0 fb of
integrated luminosity recorded by the LHCb experiment during 2011 and 2012. The
tau lepton is identified in the decay mode
. The measured values are
and
, where the first uncertainty is
statistical and the second is systematic. The correlation between these
measurements is . Results are consistent with the current average
of these quantities and are at a combined 1.9 standard deviations from the
predictions based on lepton flavor universality in the Standard Model.Comment: All figures and tables, along with any supplementary material and
additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-039.html (LHCb
public pages
Funktionelle Regulation von gap junctions und ihrer Anordnung durch das Sub-membranale Zytoskelett
Connexine formen gap junctions, die den Transfer von Ionen, Metaboliten und second messengers zwischen sich berührenden Zellen vermitteln. An vielen Funktionen der Connexine, z.B. zellulärer Transport, Plaquebildung und -stabilität sowie Kanalleitfähigkeit sind Proteine beteiligt, die an die cytoplasmatischen Domänen von Connexinen binden. Jedoch ist auch jetzt noch wenig bekannt über diese regulatorischen Proteine.In der vorliegenden Arbeit wurden neue Proteine, die am intrazellulären Transport von Connexin 43 und an der Festlegung der funktionalen Aktivität von Gap junctions unter der Plasmamembran beteiligt sind, identifiziert.Das Auftreten von Connexin43 (Cx43) in der Plasmamembran hängt von der funktionellen Aktivität der kleinen GTPasen Sar1 und ARF1 ab. Der Transport von Cx43 vom endoplasmatischen Retikulum zum Golgi-Apparat wurde durch die Expression einer GTP-restrikten Mutante des Sar1 blockiert. Die GTP-gebundene Mutante der ARF1 verhinderte den Transport des Cx43 vom Golgi-Apparat zur Plasmamembran.Drebrin, ein Actin-bindendes Protein, wurde durch einen proteomischen Ansatz als ein Partner von Cx43 identifiziert, der mit dessen terminalen COOH-Domäne interagiert. Die Drebrin-Cx43 Interaktion, in vorliegender Arbeit erstmals beschrieben, wurde durch die Kolokalisation beider endogener Proteine in Astrozyten und in Vero Zellen, mit immunopräzipitiven, elektromikroskopischen und elektrophysiologischen Untersuchungen, sowie mit Expressionsansätzen beider Proteine mit fluoreszierenden Tags" und mit FRET Analysen in lebenden Zellen bestätigt. Eine Depletion von Drebrin in Zellen mit si-RNA resultierte in einer Beeinträchtigung der Farbkopplung und der elektrischen Kopplung von Zellen mit gap junctions, in einer Internalisierung von gap junctions und des Abbaus von Cx43.Auf der Basis dieser Daten schlussfolgere ich, dass Drebrin erforderlich ist, um die Cx43-enthaltenden gap junctions in der Plasmamembran in ihrem funktionellen Zustand aufrechtzuerhalten. Es ist deshalb möglich, dass Drebrin mit gap junctions im Bereich der Zellkontakte in regulatorischer Weise auf extrazelluläre Signal interagiert. Die Neuordnung oder Störung der Interaktion zwischen Connexin43 und dem Drebrin-enthaltenden Sub-membranale-Zytoskelett weist Connexin43 auf zelluläre Abbauwege hin
Game of Zones: how actin-binding proteins organize muscle contraction
Locomotion of C. elegans requires coordinated, efficient transmission of forces generated on the
molecular scale by myosin and actin filaments in myocytes to dense bodies and the hypodermis
and cuticle enveloping body wall muscles. The complex organization of the acto-myosin scaffold
with its accessory proteins provides a fine-tuned machinery regulated by effectors that guarantees
that sarcomere units undergo controlled, reversible cycles of contraction and relaxation. Actin
filaments in sarcomeres dynamically undergo polymerization and depolymerization. In a recent
study, the actin-binding protein DBN-1, the C. elegans ortholog of human drebrin and drebrin-like
proteins, was discovered to stabilize actin in muscle cells. DBN-1 reversibly changes location
between actin filaments and myosin-rich regions during muscle contraction. Mutations in DBN-1
result in mislocalization of other actin-binding proteins. Here we discuss implications of this finding
for the regulation of sarcomere actin stability and the organization of other actin-binding proteins.peerReviewe
Drebrin-like protein DBN-1 is a sarcomere component that stabilizes actin filaments during muscle contraction
Phosphorylation of FEZ1 by Microtubule Affinity Regulating Kinases regulates its function in presynaptic protein trafficking
10.1038/srep26965SCIENTIFIC REPORTS61UNITED KINGDO
Synaptic scaffolding protein SYD-2 clusters and activates kinesin-3 UNC-104 in C. elegans
Kinesin-3 motor UNC-104/KIF1A is essential for transporting synaptic precursors to synapses. Although the mechanism of cargo binding is well understood, little is known how motor activity is regulated. We mapped functional interaction domains between SYD-2 and UNC-104 by using yeast 2-hybrid and pull-down assays and by using FRET/fluorescence lifetime imaging microscopy to image the binding of SYD-2 to UNC-104 in living Caenorhabditis elegans. We found that UNC-104 forms SYD-2-dependent axonal clusters (appearing during the transition from L2 to L3 larval stages), which behave in FRAP experiments as dynamic aggregates. High-resolution microscopy reveals that these clusters contain UNC-104 and synaptic precursors (synaptobrevin-1). Analysis of motor motility indicates bi-directional movement of UNC-104, whereas in syd-2 mutants, loss of SYD-2 binding reduces net anterograde movement and velocity (similar after deleting UNC-104's liprin-binding domain), switching to retrograde transport characteristics when no role of SYD-2 on dynein and conventional kinesin UNC-116 motility was found. These data present a kinesin scaffolding protein that controls both motor clustering along axons and motor motility, resulting in reduced cargo transport efficiency upon loss of interaction
Limiting transport steps and novel interactions of Connexin-43 along the secretory pathway
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