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\"Stroll through the famed royal parks and gardens, admire the panorama of the Thames while crossing the Millennium Bridge, enjoy a play at the historic Shakespeare's Globe or get a bird's eye view of the city from the London Eye. From Top 10 art galleries to Top 10 famous residents - discover the best of London with this easy-to-use travel guide.\"--Provided by publisher.
Book
The emerging shape of the ESCRT machinery
Key Points
Central to the function of the MVB pathway for trafficking to lysosomes are the endosomal sorting complex required for transport-0 (ESCRT-0), -I, -II and –III complexes, which are represented in all eukaryotic taxa. Ubiquitylation is the best characterised signal for entry into this pathway, and all of the ESCRTs, except for ESCRT-III, recognize ubiquitin.
The ESCRT-0 complex recruits ubiquitylated cargo to flat clathrin-coated dynamic microdomains on endosomes and is essential to recruiting ESCRT-I. The endosomal recruitment of ESCRT-0 is mediated by binding to 3-phosphoinosides, which are enriched in early endosome membranes.
ESCRT-I is built around a heterotrimeric core to which flexibly connected modules that recognize ubiquitylated cargo and the downstream ESCRT-II complex are connected. This complex is essential for intralumenal vesicle formation and vacuolar stability.
The four-subunit ESCRT-II core complex is built from winged-helix domains. The subunits link directly to the downstream VPS20 subunit of ESCRT-III, whereas the N-terminal GLUE domain of VPS36 recognizes ubiquitin, 3-phosphoinositides and, in yeast, the upstream ESCRT-I.
ESCRT-III subunits are represented in all eukaryotic taxa. These subunits heterodimerize via a long N-terminal helical hairpin to form lattices on endosomal membranes that require the AAA+ ATPase VPS4 for subsequent disassembly. The lattice has been proposed to facilitate membrane curvature and the formation of intralumenal vesicles.
De-ubiquitinases are recruited by ESCRT-III and can remove ubiquitin from cargo before and after it is committed to entry into intralumenal vesicles.
The endosomal sorting complex required for transport (ESCRT) machinery facilitates the sorting of proteins that are destined for lysosomal degradation into multivesicular bodies. Recent structural and functional studies provide new insights into the regulation of this machinery and the biogenesis of multivesicular bodies.
The past two years have seen an explosion in the structural understanding of the endosomal sorting complex required for transport (ESCRT) machinery that facilitates the trafficking of ubiquitylated proteins from endosomes to lysosomes via multivesicular bodies (MVBs). A common organization of all ESCRTs is a rigid core attached to flexibly connected modules that recognize other components of the MVB pathway. Several previously unsuspected key links between multiple ESCRT subunits, phospholipids and ubiquitin have now been elucidated, which, together with the detailed morphological analyses of ESCRT-depletion phenotypes, provide new insights into the mechanism of MVB biogenesis.
Journal Article
Activation of GCN2 by the ribosomal P-stalk
Cells dynamically adjust their protein translation profile to maintain homeostasis in changing environments. During nutrient stress, the kinase general control nonderepressible 2 (GCN2) phosphorylates translation initiation factor eIF2α, initiating the integrated stress response (ISR). To examine the mechanism of GCN2 activation, we have reconstituted this process in vitro, using purified components. We find that recombinant human GCN2 is potently stimulated by ribosomes and, to a lesser extent, by tRNA. Hydrogen/deuterium exchange–mass spectrometry (HDX-MS) mapped GCN2–ribosome interactions to domain II of the uL10 subunit of the ribosomal P-stalk. Using recombinant, purified P-stalk, we showed that this domain of uL10 is the principal component of binding to GCN2; however, the conserved 14-residue C-terminal tails (CTTs) in the P1 and P2 P-stalk proteins are also essential for GCN2 activation. The HisRS-like and kinase domains of GCN2 show conformational changes upon binding recombinant P-stalk complex. Given that the ribosomal P-stalk stimulates the GTPase activity of elongation factors during translation, we propose that the P-stalk could link GCN2 activation to translational stress, leading to initiation of ISR.
Journal Article
Immunomodulatory Role of the Extracellular Matrix Within the Liver Disease Microenvironment
Chronic liver disease when accompanied by underlying fibrosis, is characterized by an accumulation of extracellular matrix (ECM) proteins and chronic inflammation. Although traditionally considered as a passive and largely architectural structure, the ECM is now being recognized as a source of potent damage-associated molecular pattern (DAMP)s with immune-active peptides and domains. In parallel, the ECM anchors a range of cytokines, chemokines and growth factors, all of which are capable of modulating immune responses. A growing body of evidence shows that ECM proteins themselves are capable of modulating immunity either directly
ligation with immune cell receptors including integrins and TLRs, or indirectly through release of immunoactive molecules such as cytokines which are stored within the ECM structure. Notably, ECM deposition and remodeling during injury and fibrosis can result in release or formation of ECM-DAMPs within the tissue, which can promote local inflammatory immune response and chemotactic immune cell recruitment and inflammation. It is well described that the ECM and immune response are interlinked and mutually participate in driving fibrosis, although their precise interactions in the context of chronic liver disease are poorly understood. This review aims to describe the known pro-/anti-inflammatory and fibrogenic properties of ECM proteins and DAMPs, with particular reference to the immunomodulatory properties of the ECM in the context of chronic liver disease. Finally, we discuss the importance of developing novel biotechnological platforms based on decellularized ECM-scaffolds, which provide opportunities to directly explore liver ECM-immune cell interactions in greater detail.
Journal Article
St. Eom in the land of Pasaquan : the life and times and art of Eddie Owens Martin
Self-taught Georgia artist Eddie Owens Martin (1908-86), known as St. EOM, created a visionary art site called Pasaquan in the mid-1950s in Marion County, Georgia. Covering seven acres, this evocative and fanciful site has captured the imaginations of thousands of visitors. Pasaquan includes six buildings connected by concrete walls, all of which are adorned with the artist's vibrant, psychedelic folk art of bold, transfixing patterns, spiritual and tribal imagery, and exuberant depictions of nature. According to St. EOM, his art arose from a vision he experienced in his mid-twenties, while suffering from a high fever. The first of many visionary experiences, it featured a godlike being who offered to be Martin's spiritual guide. Subsequent visions inspired him to begin making art and, eventually, to create a spiritual compound dedicated to a peaceful future for humankind. St. EOM enlarged his house to twice its original size by adding a long rear section covered inside and out with his rainbow-hued murals, mandalas, and relief sculptures. On the grounds he built a series of structures including a circular dance platform, some small temples, several totems, and a two-story pagoda, all in his wildly ornamental style. He also created more than two thousand freestanding pieces, including paintings, sculptures, and drawings. In the thirty years since St. EOM's death, the Pasaquan Preservation Society worked to preserve the compound, which had fallen into neglect. In 2014 the Kohler Foundation and Columbus State University partnered with the society to restore the visionary art site for future generations. It is now listed on the National Register of Historic Places.
Book
Structure and flexibility of the endosomal Vps34 complex reveals the basis of its function on membranes
During intracellular membrane trafficking, large protein complexes regulate and adapt the activity of signal transducer enzymes such as the class III phosphatidylinositol 3-kinase Vps34. These large enzyme complexes are present in all eukaryotic cells, having widespread importance in neurodegeneration, aging, and cancer; however, a structural understanding has been lacking. Rostislavleva et al. provide atomic-resolution insights into the structures of the Vps34-containing protein complexes required for autophagy, endocytic sorting, and cytokinesis. The V-shaped complexes can undergo opening motions, which allows them to adapt to and phosphorylate membranes. Science , this issue p. 10.1126/science.aac7365 An atomic-resolution analysis provides insight into protein complexes required for autophagy, endocytic sorting, and cytokinesis. Phosphatidylinositol 3-kinase Vps34 complexes regulate intracellular membrane trafficking in endocytic sorting, cytokinesis, and autophagy. We present the 4.4 angstrom crystal structure of the 385-kilodalton 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. We used hydrogen-deuterium exchange mass spectrometry (HDX-MS) to reveal conformational changes accompanying membrane binding and identify a Vps30 loop that is critical for the ability of complex II to phosphorylate giant liposomes on which complex I is inactive.
Journal Article
Oncogenic mutations mimic and enhance dynamic events in the natural activation of phosphoinositide 3-kinase p110α (PIK3CA)
The p110α catalytic subunit (PIK3CA) is one of the most frequently mutated genes in cancer. We have examined the activation of the wild-type p110α/p85α and a spectrum of oncogenic mutants using hydrogen/deuterium exchange mass spectrometry (HDX-MS). We find that for the wild-type enzyme, the natural transition from an inactive cytosolic conformation to an activated form on membranes entails four distinct events. Analysis of oncogenic mutations shows that all up-regulate the enzyme by enhancing one or more of these dynamic events. We provide the first insight into the activation mechanism by mutations in the linker between the adapter-binding domain (ABD) and the Ras-binding domain (RBD) (G106V and G118D). These mutations, which are common in endometrial cancers, enhance two of the natural activation events: movement of the ABD and ABD–RBD linker relative to the rest of the catalytic subunit and breaking the C2–iSH2 interface on binding membranes. C2 domain mutants (N345K and C420R) also mimic these events, even in the absence of membranes. A third event is breaking the nSH2–helical domain contact caused by phosphotyrosine-containing peptides binding to the enzyme, which is mimicked by a helical domain mutation (E545K). Interaction of the C lobe of the kinase domain with membranes is the fourth activation event, and is potentiated by kinase domain mutations (e.g., H1047R). All mutations increased lipid binding and basal activity, even mutants distant from the membrane surface. Our results elucidate a unifying mechanism in which diverse PIK3CA mutations stimulate lipid kinase activity by facilitating allosteric motions required for catalysis on membranes.
Journal Article