FEBS Letters最新文献

Clioquinol has been thought of as the causative drug of subacute myelo-optic neuropathy (SMON). The underlying mechanisms of clioquinol toxicity, however, have not been elucidated in detail. Here, we revealed that clioquinol (20 μm) suppressed the expression of SCO1 and SCO2 copper chaperones for mitochondrial respiratory chain Complex IV (cytochrome c oxidase) in SH-SY5Y neuroblastoma cells. The assembly of Complex IV components and Complex IV activity were suppressed in clioquinol-treated cells. Clioquinol (10-50 μm) decreased cellular ATP levels in glucose-free media. Clioquinol (10-50 μm) induced OMA1 mitochondrial protease-dependent degradation of the dynamin-related GTPase OPA1 and suppressed the expression of CHCHD10 and CHCHD2 involved in the maintenance of cristae structure. These results suggest that mitochondrial toxicity is one of the mechanisms of clioquinol-induced neuronal cell death.

α2 → 8 polysialic acid (polySia), the capsular polysaccharide on Neisseria meningitidis serogroup B and Escherichia coli K1, elicits poor immunogenic properties. A solution structure might clarify the cause. From X-ray and neutron small-angle scattering, we find that the solution supramolecular structure of polySia exhibits parallel-chain binding. Also, striking structural changes occur upon the addition of calcium to these solutions but still with the parallel motif. The major histocompatibility complex requires entities in the molecular weight range of 600-3000 Da, but the solution structures determined here argue that in endosomes polySia oligomers of the correct size to be immunologically effective are instead bound up as parallel chains. This is expected to reduce the possible concentrations of the effective oligomers and so reduce the immunogenic capability of α2 → 8 polysialic acid.

Immunoglobulin G1 (IgG1) antibodies undergo denaturation in acidic conditions, resulting in an alternatively folded state (AFS). The AFS structure is more compact than the native state. However, the prevalence of AFS in other subclasses remains largely unexplored. This study provides evidence that humanized IgG4 can also adopt the AFS structure, as demonstrated through size-exclusion chromatography coupled with small-angle X-ray scattering (SEC-SAXS) analysis. These findings suggest that the anomalous compaction of immunoglobulins G (IgGs) is resilient to variations in sequence and structure among subclasses.

The phycobilisome (PBS) captures light energy and transfers it to photosystem I (PSI) and photosystem II (PSII). Which and how many copies of protein subunits in PBSs, PSI, and PSII remain unbound in thylakoids are unknown. Here, quantitative mass spectrometry (QMS) was used to quantify substantial pools of free extrinsic subunits of PSII and PSI. Interestingly, the membrane intrinsic PsaL is 3-fold higher than PsaA/B. This scenario complements the static structures of these complexes as revealed by X-ray crystallography and cryo-EM. The ratios of ApcG and photoprotective OCP over PBS indicate a pool of extra ApcG. The 2.5 ratio of CpcG-PBS over CpcL-PBS improves our understanding of these light-harvesting complexes involved in energy capture and photoprotection in cyanobacteria. Impact statement Our study presents the first quantitative inquiry of the free pools of proteins associated with the three major photosynthetic complexes in Synechocystis 6803. This study increases our understanding of the unbound thylakoid proteome, guiding future research into the functions of these proteins, which will facilitate efforts to enhance photosynthetic efficiency.

The ribosome-associated endoribonuclease Rae1 cleaves the Bacillus subtilis yrzI operon mRNA in a translation-dependent manner. This operon encodes up to four small peptides, S1027, YrzI, S1025, and S1024, whose functions are unknown. Here, we identified the function of YrzI and S1025 and deciphered the degradation pathways of the yrzI polycistronic mRNA. We show that YrzI is toxic at high concentrations, but co-expression with S1025 abolishes its toxicity, and that, in the absence of Rae1, S1025 is the major antidote to the YzI toxin. We show that a highly stable mRNA species containing the YrzI and S1025 open reading frames results from endoribonucleolytic cleavage upstream of yrzI followed by the arrest of 5'-exoribonucleolytic processing by ribosomes bound to its exceptionally strong Shine-Dalgarno sequence. Degradation of this mRNA requires either translation-dependent cleavage within S1025 by Rae1 or direct attack from the structured 3'-end by 3'-exoribonucleases. Neither pathway is common for a B. subtilis mRNA.

We examine biologists leaving science in 38 OECD countries in the past two decades. In a cohort-based and longitudinal fashion, we follow individuals over time, from their first publication (N = 86 178). We examine four disciplines: AGRI (agricultural, biological sciences), BIO (biochemistry, genetics, molecular biology), IMMU (immunology, microbiology), and NEURO (neuroscience). Our Kaplan–Meier survival analysis of BIO shows that 60% of women are still in science after 5 years, 40% after 10 years, and only 20% after 19 years. Women in BIO are 23.26% more likely than men to leave science after 10 years and 39.74% after 19 years. Gender differences increase consistently in later career stages. They are high, but comparing the 2000 and 2010 cohorts, have slightly decreased over time.

Branched-chain amino acids (BCAA) are essential requirements for overall protein turnover, signalling and energy balance, and dysregulation of their metabolic pathway has been associated with many pathophysiological events. Despite the importance of BCAA in human health, our understanding of their metabolic regulation is limited. Here, we present evidence that G protein-coupled oestrogen receptor (GPER) activation inhibits the key BCAA metabolic regulatory enzyme branched-chain α-keto acid dehydrogenase complex (BCKDH) by phosphorylating S293. Inhibition of BCKDH results in leucine, isoleucine and valine accumulation in cells. Interestingly, GPER did not alter the levels of the kinase BCKDK and the phosphatase PPM1K, which regulate BCKDH activity, but activated MAPK signalling. Using gene silencing, we identified that JNK intercedes GPER-mediated BCKDH inhibition. Together, our results demonstrate that GPER inhibits BCAA metabolism through JNK signalling.

Importin family nucleocytoplasmic transport receptors share thousands of cargo proteins. To elucidate cell regulatory mechanisms via transport regulation, we analyzed the levels of transport receptors by western blotting and quantified the total cellular and nuclear proteins during monocyte-to-macrophage differentiation of THP-1 cells using mass spectrometry. Importin-α1 decreased and importin-α5 increased during the differentiation. Cell cycle-related proteins decreased in both whole cells and nuclei, and proteasome-related proteins increased in the nuclei but not in whole cells. During the differentiation with importin-α1 overexpression, the nuclear levels of some cell division-related proteins recovered, and with importin-α5 knockdown, proteasome assembly factors decreased in the nuclei. In this differentiation, transport receptors reduce unnecessary nuclear proteins by abating import and promoting nuclear proteasomal degradation. This study demonstrates the importance of global nuclear transport control in cell regulation.

The protein Tau accumulates in the brain as insoluble deposits in a number of neurodegenerative diseases called tauopathies. In vitro work studying the properties of reconstituted tau assemblies has played a major role in understanding the fundamental mechanisms underlying tauopathies. Yet, in our view, the extent to which tau in vitro models represent the assemblies found in the brain is not sufficiently addressed. Here, we provide an overview of the procedures used to form tau amyloids in vitro and we discuss their similarities and differences with brain deposits. We emphasize that, to date, further work is needed to establish how to form accurate models of tau deposits with recombinant protein, let alone how to represent disease-specific properties that discriminate tauopathies.

Toll-like receptors (TLRs) are important players in the innate immune system. Binding of pathogen-related molecules to the extracellular domains of TLRs initiates signalosome assembly, a key event in signal transduction. Despite extensive research on individual receptor domains, the mechanism of signalosome assembly remains unclear. Recent evidence suggests that the intracellular TIR domain of TLR1 binds zinc ions, with cysteines playing a pivotal role in binding and receptor activation. This study explores the zinc-binding ability of the TLR2 TIR domain (TLR2_TIR). We found that TLR2_TIR binds zinc with nanomolar affinity through its cysteine residues. Two of them, C673 and C713, are essential for receptor activation. These results suggest that zinc may be involved in the initiation of signalosome assembly.