We demonstrate that megaton-mass neutrino telescopes are able to observe the signal from long-lived particles beyond the Standard Model, in particular the stau, the supersymmetric partner of the tau ...lepton. Its signature is an excess of charged particle tracks with horizontal arrival directions and energy deposits between 0.1 and 1 TeV inside the detector. We exploit this previously-overlooked signature to search for stau particles in the publicly available IceCube data. The data shows no evidence of physics beyond the Standard Model. We derive a new lower limit on the stau mass of 320 GeV (95% C.L.) and estimate that this new approach, when applied to the full data set available to the IceCube collaboration, will reach word-leading sensitivity to the stau mass (mτ˜=450GeV).
Phys. Rev. Lett. 129 (2022) 1, 011804 We report a search for nonstandard neutrino interactions (NSI) using eight
years of TeV-scale atmospheric muon neutrino data from the IceCube Neutrino
...Observatory. By reconstructing incident energies and zenith angles for
atmospheric neutrino events, this analysis presents unified confidence
intervals for the NSI parameter $\epsilon_{\mu \tau}$. The best-fit value is
consistent with no NSI at a p-value of 25.2%. With a 90% confidence interval of
$-0.0041 \leq \epsilon_{\mu \tau} \leq 0.0031$ along the real axis and similar
strength in the complex plane, this result is the strongest constraint on any
NSI parameter from any oscillation channel to date.
Systemic antibody light chain (AL) amyloidosis is characterized by deposition of amyloid fibrils. Prior to fibril formation, soluble oligomeric AL protein has a direct cytotoxic effect on ...cardiomyocytes. We focus on the patient derived λ-III AL variable domain FOR005 which is mutated at five positions with respect to the closest germline protein. Using solution-state NMR spectroscopy, we follow the individual steps involved in protein misfolding from the native to the amyloid fibril state. Unfavorable mutations in the complementary determining regions introduce a strain in the native protein structure which yields partial unfolding. Driven by electrostatic interactions, the protein converts into a high molecular weight, oligomeric, molten globule. The high local concentration of aggregation prone regions in the oligomer finally catalyzes the conversion into fibrils. The topology is determined by balanced electrostatic interactions in the fibril core implying a 180° rotational switch of the beta-sheets around the conserved disulfide bond.
One‐third of the human proteome is comprised of membrane proteins, which are particularly vulnerable to misfolding and often require folding assistance by molecular chaperones. Calnexin (CNX), which ...engages client proteins via its sugar‐binding lectin domain, is one of the most abundant ER chaperones, and plays an important role in membrane protein biogenesis. Based on mass spectrometric analyses, we here show that calnexin interacts with a large number of nonglycosylated membrane proteins, indicative of additional nonlectin binding modes. We find that calnexin preferentially bind misfolded membrane proteins and that it uses its single transmembrane domain (TMD) for client recognition. Combining experimental and computational approaches, we systematically dissect signatures for intramembrane client recognition by calnexin, and identify sequence motifs within the calnexin TMD region that mediate client binding. Building on this, we show that intramembrane client binding potentiates the chaperone functions of calnexin. Together, these data reveal a widespread role of calnexin client recognition in the lipid bilayer, which synergizes with its established lectin‐based substrate binding. Molecular chaperones thus can combine different interaction modes to support the biogenesis of the diverse eukaryotic membrane proteome.
Synopsis
Calnexin is a membrane‐integral chaperone that acts on glycosylated proteins. This study shows that its transmembrane domain is also involved in substrate binding, defines how intramembrane substrate recognition occurs, and reveals that this additional binding mode supports chaperoning.
The mass‐spectrometric interactome of calnexin contains many non‐glycosylated membrane proteins.
Calnexin can bind membrane protein substrates in the lipid bilayer via its own transmembrane domain.
A systematic analysis reveals how calnexin recognizes particular features within its clients in the membrane.
Intra‐membrane client recognition synergizes with sugar‐based recognition of calnexin clients to protect labile chaperone substrates.
Chaperoning of misfolded membrane proteins by calnexin in the ER involves not only lectin‐based glycan binding, but also direct transmembrane domain interactions within the lipid bilayer.
A fundamental step in membrane protein biogenesis is their integration into the lipid bilayer with a defined orientation of each transmembrane segment. Despite this, it remains unclear how cells ...detect and handle failures in this process. Here we show that single point mutations in the membrane protein connexin 32 (Cx32), which cause Charcot-Marie-Tooth disease, can cause failures in membrane integration. This leads to Cx32 transport defects and rapid degradation. Our data show that multiple chaperones detect and remedy this aberrant behavior: the ER-membrane complex (EMC) aids in membrane integration of low-hydrophobicity transmembrane segments. If they fail to integrate, these are recognized by the ER-lumenal chaperone BiP. Ultimately, the E3 ligase gp78 ubiquitinates Cx32 proteins, targeting them for degradation. Thus, cells use a coordinated system of chaperones for the complex task of membrane protein biogenesis, which can be compromised by single point mutations, causing human disease.
We have measured the flux of cosmic muons in the Laboratori Nazionali del Gran Sasso at 3800\,m\,w.e. to be \((3.432 \pm 0.003)\cdot 10^{-4}\,\mathrm{{m^{-2}s^{-1}}}\) based on ten years of Borexino ...data acquired between May 2007 and May 2017. A seasonal modulation with a period of \((366.3 \pm 0.6)\,\mathrm{d}\) and a relative amplitude of \((1.36 \pm0.04)\%\) is observed. The phase is measured to be \((181.7 \pm 0.4)\,\mathrm{d}\), corresponding to a maximum at the 1\(^\mathrm{st}\) of July. Using data inferred from global atmospheric models, we show the muon flux to be positively correlated with the atmospheric temperature and measure the effective temperature coefficient \(\alpha_\mathrm{T} = 0.90 \pm 0.02\). The origin of cosmic muons from pion and kaon decays in the atmosphere allows to interpret the effective temperature coefficient as an indirect measurement of the atmospheric kaon-to-pion production ratio \(r_{\mathrm{K}/\pi} = 0.11^{+0.11}_{-0.07}\) for primary energies above \(18\,\mathrm{TeV}\). We find evidence for a long-term modulation of the muon flux with a period of \(\sim 3000\,\mathrm{d}\) and a maximum in June 2012 that is not present in the atmospheric temperature data. A possible correlation between this modulation and the solar activity is investigated. The cosmogenic neutron production rate is found to show a seasonal modulation in phase with the cosmic muon flux but with an increased amplitude of \((2.6 \pm 0.4)\%\).
Catechol-containing natural products are common constituents of foods, drinks, and drugs. Natural products carrying this motif are often associated with beneficial biological effects such as ...anticancer activity and neuroprotection. However, the molecular mode of action behind these properties is poorly understood. Here, we apply a mass spectrometry-based competitive chemical proteomics approach to elucidate the target scope of catechol-containing bioactive molecules from diverse foods and drugs. Inspired by the protein reactivity of catecholamine neurotransmitters, we designed and synthesised a broadly reactive minimalist catechol chemical probe based on dopamine. Initial labelling experiments in live human cells demonstrated broad protein binding by the probe, which was largely outcompeted by its parent compound dopamine. Next, we investigated the competition profile of a selection of biologically relevant catechol-containing substances. With this approach, we characterised the protein reactivity and the target scope of dopamine and ten biologically relevant catechols. Strikingly, proteins associated with the endoplasmic reticulum (ER) were among the main targets. ER stress assays in the presence of reactive catechols revealed an activation of the unfolded protein response (UPR). The UPR is highly relevant in oncology and cellular resilience, which may provide an explanation of the health-promoting effects attributed to many catechol-containing natural products.
Using a competitive chemoproteomics approach, we profile the proteome modified by catechols from foods, drinks, and drugs.
We report a search for nonstandard neutrino interactions (NSI) using eight years of TeV-scale atmospheric muon neutrino data from the IceCube Neutrino Observatory. By reconstructing incident energies ...and zenith angles for atmospheric neutrino events, this analysis presents unified confidence intervals for the NSI parameter \(\epsilon_{\mu \tau}\). The best-fit value is consistent with no NSI at a p-value of 25.2%. With a 90% confidence interval of \(-0.0041 \leq \epsilon_{\mu \tau} \leq 0.0031\) along the real axis and similar strength in the complex plane, this result is the strongest constraint on any NSI parameter from any oscillation channel to date.
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