39 research outputs found
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Membrane characteristics tune activities of endosomal and autophagic human VPS34 complexes.
The lipid kinase VPS34 orchestrates diverse processes, including autophagy, endocytic sorting, phagocytosis, anabolic responses and cell division. VPS34 forms various complexes that help adapt it to specific pathways, with complexes I and II being the most prominent ones. We found that physicochemical properties of membranes strongly modulate VPS34 activity. Greater unsaturation of both substrate and non-substrate lipids, negative charge and curvature activate VPS34 complexes, adapting them to their cellular compartments. Hydrogen/deuterium exchange mass spectrometry (HDX-MS) of complexes I and II on membranes elucidated structural determinants that enable them to bind membranes. Among these are the Barkor/ATG14L autophagosome targeting sequence (BATS), which makes autophagy-specific complex I more active than the endocytic complex II, and the Beclin1 BARA domain. Interestingly, even though Beclin1 BARA is common to both complexes, its membrane-interacting loops are critical for complex II, but have only a minor role for complex I
Structure and flexibility of the endosomal Vps34 complex reveals the basis of its function on membranes
Phosphatidylinositol 3-kinase Vps34 complexes regulate intracellular membrane trafficking in endocytic sorting, cytokinesis and autophagy. We present the 4.4 Å crystal structure of the 385 kDa endosomal complex II (PIK3C3-CII), consisting of Vps34, Vps15 (p150), Vps30/Atg6 (Beclin 1) and Vps38 (UVRAG). The subunits form a Y-shaped complex, centered on the Vps34 C2 domain. Vps34 and Vps15 intertwine in one arm where the Vps15 kinase domain engages the Vps34 activation loop to regulate its activity. Vps30 and Vps38 form the other arm that brackets the Vps15/Vps34 heterodimer, suggesting a path for complex assembly. Hydrogen-Deuterium Exchange Mass Spectrometry (HDX-MS) revealed conformational changes accompanying membrane binding and identified a Vps30 loop that is critical for the ability of complex II to phosphorylate giant liposomes on which complex I is inactive
Polyglutamine tracts regulate beclin 1-dependent autophagy
Nine neurodegenerative diseases are caused by expanded polyglutamine (polyQ) tracts in different proteins, such as huntingtin in Huntington's disease and ataxin 3 in spinocerebellar ataxia type 3 (SCA3). Age at onset of disease decreases with increasing polyglutamine length in these proteins and the normal length also varies. PolyQ expansions drive pathogenesis in these diseases, as isolated polyQ tracts are toxic, and an N-terminal huntingtin fragment comprising exon 1, which occurs as a result of alternative splicing, causes toxicity. Although such mutant proteins are prone to aggregation, toxicity is also associated with soluble forms of the proteins. The function of the polyQ tracts in many normal cytoplasmic proteins is unclear. One such protein is the deubiquitinating enzyme ataxin 3 (refs 7, 8), which is widely expressed in the brain. Here we show that the polyQ domain enables wild-type ataxin 3 to interact with beclin 1, a key initiator of autophagy. This interaction allows the deubiquitinase activity of ataxin 3 to protect beclin 1 from proteasome-mediated degradation and thereby enables autophagy. Starvation-induced autophagy, which is regulated by beclin 1, was particularly inhibited in ataxin-3-depleted human cell lines and mouse primary neurons, and in mice. This activity of ataxin 3 and its polyQ-mediated interaction with beclin 1 was competed for by other soluble proteins with polyQ tracts in a length-dependent fashion. This competition resulted in impairment of starvation-induced autophagy in cells expressing mutant huntingtin exon 1, and this impairment was recapitulated in the brains of a mouse model of Huntington's disease and in cells from patients. A similar phenomenon was also seen with other polyQ disease proteins, including mutant ataxin 3 itself. Our data thus describe a specific function for a wild-type polyQ tract that is abrogated by a competing longer polyQ mutation in a disease protein, and identify a deleterious function of such mutations distinct from their propensity to aggregate.We thank the Wellcome Trust (Principal Research Fellowship to D.C.R. (095317/Z/11/Z), Wellcome Trust Strategic Grant to Cambridge Institute for Medical Research (100140/Z/12/Z)), National Institute for Health Research Biomedical Research Centre at Addenbrooke’s Hospital, and Addenbrooke’s Charitable Trust and Federation of European Biochemical Societies (FEBS Long-Term Fellowship to A.A.) for funding; R. Antrobus for mass spectrometry analysis; S. Luo for truncated HTT constructs; M. Jimenez-Sanchez and C. Karabiyik for assistance with the primary mouse cell cultures; and J. Lim and Z. Ignatova for reagents
The “Female presence” in Safeguarding and Continuing the Heritage of Historian V.I. Guerrier: E.V. Guerrier
This article considers the main milestones in the life of Elena Vladimirovna Guerrier (1868–1942), the daughter of the prominent Russian historian V.I. Guerrier. She was highly educated and fluent in four European languages, including German. During World War I, she was in Germany where she cemented her status as a fervent patriot of Russia and made every attempt to repatriate Russian subjects. E.V. Guerrier became widely respected for her contributions in the fields of school education and philanthropy. The recognition she received on the 25th anniversary of her hard work highlights that her public endeavors and initiatives were highly appreciated. After the October Revolution in 1917, E.V. Guerrier went through difficult times. She took care of her ailing father, who eventually succumbed to his illness. She was also arrested twice and served some time at Butyrka prison. In an attempt to integrate into Soviet society politically, E.V. Guerrier worked as a librarian and researcher at Lenin’s State Library for over ten years. However, due to her poor health, she retired in 1928. Until her death in 1942, she organized and safeguarded V.I. Guerrier’s scientific heritage by thoroughly revising his articles. She rewrote her father’s memoirs, which is a valuable source of information about the establishment of women’s higher education in Russia
Metamorphoses of the Republican Idea in Germany
В статье рассматривается трансформация республиканской идеи в Германии с эпохи Просвещения до начала XX в. Автор показывает, что в конце XVII – XVIII в. республика не воспринималась как форма правления, а интерпретировалась в духе классического республиканизма (res publica / civitas). В XIX в. немецкие мыслители и политики демонстрировали гетерогенное отношение к республике: в раннегерманском либерализме она интерпретировалась в значительной степени в духе рациональных схем Просвещения и не рассматривалась в практической плоскости. Республика стала восприниматься как форма правления благодаря демократам, считавшим ее идеальной формой правления. Но либеральный лагерь и его лидер Макс Вебер приняли республику, когда она уже состоялась (1919 г.).The article describes the transformation of the republican idea in Germany from the Enlightenment till the early twentieth century. The author demonstrates that in the late seventeenth and early eighteenth centuries, a republic was understood not as a governmental form, but was rather interpreted in the vein of classical republicanism (res publica / civitas). German thinkers and politicians of the nineteenth century had heterogenic attitudes to a republic: the early German liberalism interpreted it mostly in the spirit of rational Enlightenment schemes, rather than in the practical focus. Republic was declared as a governmental form due to democrats, who consider it an ideal form of rule. But liberals and their leader Max Weber accepted a republic only after it had succeeded (1919).Исследование выполнено при поддержке Российского научного фонда и Немецкого научно-исследовательского сообщества, проект № 19-48-04112 «Русский республиканизм от Средневековья до конца XX в.»
Sicherheitskulturen im Vergleich
Dass sich die Vorstellungen von innerer und äußerer Sicherheit in Westeuropa und Russland unterscheiden, zeigt aktuell die Krise der Ukraine. Dieser Band russischer und deutscher Forscher gibt Einblick in die jeweiligen Konzepte
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Membrane characteristics tune activities of endosomal and autophagic human VPS34 complexes
The lipid kinase VPS34 orchestrates diverse processes, including autophagy, endocytic sorting, phagocytosis, anabolic responses and cell division. VPS34 forms various complexes that help adapt it to specific pathways, with complexes I and II being the most prominent ones. We found that physicochemical properties of membranes strongly modulate VPS34 activity. Greater unsaturation of both substrate and non-substrate lipids, negative charge and curvature activate VPS34 complexes, adapting them to their cellular compartments. Hydrogen/deuterium exchange mass spectrometry (HDX-MS) of complexes I and II on membranes elucidated structural determinants that enable them to bind membranes. Among these are the Barkor/ATG14L autophagosome targeting sequence (BATS), which makes autophagy-specific complex I more active than the endocytic complex II, and the Beclin1 BARA domain. Interestingly, even though Beclin1 BARA is common to both complexes, its membrane-interacting loops are critical for complex II, but have only a minor role for complex I
Next-generation electron microscopy in autophagy research
Autophagy is the process whereby cytosol, organelles, and inclusions are taken up in a double-membrane vesicle known as the autophagosome, and transported to the lysosome for destruction and recycling. Electron microscopy (EM) led to the discovery of autophagy in the 1950s and has been a central part of its characterization ever since. New capabilities in single particle EM studies of the autophagy machinery are beginning to provide exciting insights into the mechanisms of autophagosome initiation, growth, and substrate targeting. These include EM structures at various resolutions of part of the Atg1 protein kinase complex and all of the class III phosphatidylinositol 3-phosphate complex I that initiate autophagy; the mTORC1 complex that regulates autophagy initiation; the Ape1 particle, a major substrate for selective autophagy in yeast; and p62, a mammalian selective autophagy adaptors. Equally exciting are the prospects for increased resolution and insight into autophagosome formation in cells from advances in cryo-EM tomography and focused ion beam-scanning electron microscopy (FIB-SEM). This review considers recent accomplishments, prospects for progress, and remaining obstacles that still need to be overcome