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"Virgil"
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Visualization of arrestin recruitment by a G-protein-coupled receptor
Single-particle electron microscopy and hydrogen–deuterium exchange mass spectrometry are used to characterize the structure and dynamics of a G-protein-coupled receptor–arrestin complex.
An arrestin–GPCR complex structure
Much has been learned about the structure of G-protein-coupled receptors (GCPRs) over the past seven years, but we still don't know what an activated GPCR looks like when it is bound to a β-arrestin. (Arrestins are cellular mediators with a broad range of functions, many of them involving GPCRs.) In this study the authors use single-particle electron microscopy and hydrogen–deuterium exchange mass spectrometry to characterize the structure and dynamics of a GPCR–arrestin complex. Their data support a 'biphasic' mechanism, in which the arrestin initially interacts with the phosphorylated carboxy terminus of the GPCR before re-arranging to more fully engage the membrane protein in a signalling-competent conformation.
G-protein-coupled receptors (GPCRs) are critically regulated by β-arrestins, which not only desensitize G-protein signalling but also initiate a G-protein-independent wave of signalling
1
,
2
,
3
,
4
,
5
. A recent surge of structural data on a number of GPCRs, including the β
2
adrenergic receptor (β
2
AR)–G-protein complex, has provided novel insights into the structural basis of receptor activation
6
,
7
,
8
,
9
,
10
,
11
. However, complementary information has been lacking on the recruitment of β-arrestins to activated GPCRs, primarily owing to challenges in obtaining stable receptor–β-arrestin complexes for structural studies. Here we devised a strategy for forming and purifying a functional human β
2
AR–β-arrestin-1 complex that allowed us to visualize its architecture by single-particle negative-stain electron microscopy and to characterize the interactions between β
2
AR and β-arrestin 1 using hydrogen–deuterium exchange mass spectrometry (HDX-MS) and chemical crosslinking. Electron microscopy two-dimensional averages and three-dimensional reconstructions reveal bimodal binding of β-arrestin 1 to the β
2
AR, involving two separate sets of interactions, one with the phosphorylated carboxy terminus of the receptor and the other with its seven-transmembrane core. Areas of reduced HDX together with identification of crosslinked residues suggest engagement of the finger loop of β-arrestin 1 with the seven-transmembrane core of the receptor. In contrast, focal areas of raised HDX levels indicate regions of increased dynamics in both the N and C domains of β-arrestin 1 when coupled to the β
2
AR. A molecular model of the β
2
AR–β-arrestin signalling complex was made by docking activated β-arrestin 1 and β
2
AR crystal structures into the electron microscopy map densities with constraints provided by HDX-MS and crosslinking, allowing us to obtain valuable insights into the overall architecture of a receptor–arrestin complex. The dynamic and structural information presented here provides a framework for better understanding the basis of GPCR regulation by arrestins.
Journal Article
The Ebola Virus Interferon Antagonist VP24 Directly Binds STAT1 and Has a Novel, Pyramidal Fold
Ebolaviruses cause hemorrhagic fever with up to 90% lethality and in fatal cases, are characterized by early suppression of the host innate immune system. One of the proteins likely responsible for this effect is VP24. VP24 is known to antagonize interferon signaling by binding host karyopherin α proteins, thereby preventing them from transporting the tyrosine-phosphorylated transcription factor STAT1 to the nucleus. Here, we report that VP24 binds STAT1 directly, suggesting that VP24 can suppress at least two distinct branches of the interferon pathway. Here, we also report the first crystal structures of VP24, derived from different species of ebolavirus that are pathogenic (Sudan) and nonpathogenic to humans (Reston). These structures reveal that VP24 has a novel, pyramidal fold. A site on a particular face of the pyramid exhibits reduced solvent exchange when in complex with STAT1. This site is above two highly conserved pockets in VP24 that contain key residues previously implicated in virulence. These crystal structures and accompanying biochemical analysis map differences between pathogenic and nonpathogenic viruses, offer templates for drug design, and provide the three-dimensional framework necessary for biological dissection of the many functions of VP24 in the virus life cycle.
Journal Article
Self-esteem
\"In this edited collection a distinguished set of contributors present a broad overview of psychological research on self-esteem. Each chapter is written by leading experts in the field, and surveys current research on a particular issue concerning self-esteem. Together, the chapters provide a comprehensive overview of one of the most popular topics in psychology. Each chapter presents an in-depth review of particular issues concerning self-esteem, such as the connection that self-esteem has with the self-concept and psychological adjustment. A number of further topics are covered in the book, including: - How individuals pursue self-esteem - The developmental changes in feelings of self-worth over the life span. - The existence of multiple forms of high self-esteem - The role that self-esteem plays as an interpersonal signal - The protective properties associated with the possession of high self-esteem This collection of state-of-the-art reviews of key areas of the psychological literature on self-esteem will be of great interest to researchers, and academics, and also to graduate and advanced undergraduate students of social psychology\"-- Provided by publisher.
Book
Bias-free solar syngas production by integrating a molecular cobalt catalyst with perovskite–BiVO4 tandems
The photoelectrochemical (PEC) production of syngas from water and CO
2
represents an attractive technology towards a circular carbon economy. However, the high overpotential, low selectivity and cost of commonly employed catalysts pose challenges for this sustainable energy-conversion process. Here we demonstrate highly tunable PEC syngas production by integrating a cobalt porphyrin catalyst immobilized on carbon nanotubes with triple-cation mixed halide perovskite and BiVO
4
photoabsorbers. Empirical data analysis is used to clarify the optimal electrode selectivity at low catalyst loadings. The perovskite photocathodes maintain selective aqueous CO
2
reduction for one day at light intensities as low as 0.1 sun, which provides pathways to maximize daylight utilization by operating even under low solar irradiance. Under 1 sun irradiation, the perovskite–BiVO
4
PEC tandems sustain bias-free syngas production coupled to water oxidation for three days. The devices present solar-to-H
2
and solar-to-CO conversion efficiencies of 0.06 and 0.02%, respectively, and are able to operate as standalone artificial leaves in neutral pH solution.
Photoelectrochemical production of syngas from water and CO
2
is technologically attractive but overpotentials, low selectivity and catalyst cost remain challenging. Tunable syngas production integrating cobalt porphyrin catalysts with perovskite and BiVO
4
photoabsorbers is now shown.
Journal Article
الأنيادة
الإنيادة ملحمة شعرية لاتينية تدون أحداثا تعتبر، كما تعتبر الأوذيسة، تتمة لأحداث الإلياذة. ومع أن مؤلف الملحمتين السابقتين هو هوميروس اليوناني، ومؤلف الإنيادة هو فرجيل الروماني فإنها تتصل ببعضها اتصالا وثيقا إذ إنها تتابع قصة الأمير الطروادي انياس الذي نجا بعد سقوط مدينته طروادة واستقر في غربي إيطاليا. والإنيادة ثالث أشعار فرجيل، كما أنها أطولها وآخرها، وهي تروي قصصا أسطورية تصور الشعب الروماني قبل تأسيس روما بزمن طويل. وقد نظمت بطريقة الشعر البطولي الذي عرف في القرون القديمة. وكانت الإنيادة لسنين طويلة الكتاب الرئيسي لعالم الغرب، وكان يعاد طبعها مرة كل عام على الأقل. فكانت بذلك أكثر الكتب تداولا في أوروبا وأشهرها منذ أيام الرومان.
Book
Impact of climate change on the transition of Neanderthals to modern humans in Europe
Two speleothem stable isotope records from East-Central Europe demonstrate that Greenland Stadial 12 (GS12) and GS10—at 44.3–43.3 and 40.8–40.2 ka—were prominent intervals of cold and arid conditions. GS12, GS11, and GS10 are coeval with a regional pattern of culturally (near-)sterile layers within Europe’s diachronous archeologic transition from Neanderthals to modern human Aurignacian. Sterile layers coeval with GS12 precede the Aurignacian throughout the middle and upper Danube region. In some records from the northern Iberian Peninsula, such layers are coeval with GS11 and separate the Châtelperronian from the Aurignacian. Sterile layers preceding the Aurignacian in the remaining Châtelperronian domain are coeval with GS10 and the previously reported 40.0- to 40.8-ka cal BP [calendar years before present (1950)] time range of Neanderthals’ disappearance from most of Europe. This suggests that ecologic stress during stadial expansion of steppe landscape caused a diachronous pattern of depopulation of Neanderthals, which facilitated repopulation by modern humans who appear to have been better adapted to this environment. Consecutive depopulation–repopulation cycles during severe stadials of the middle pleniglacial may principally explain the repeated replacement of Europe’s population and its genetic composition.
Journal Article
Human autoinflammatory disease reveals ELF4 as a transcriptional regulator of inflammation
Transcription factors specialized to limit the destructive potential of inflammatory immune cells remain ill-defined. We discovered loss-of-function variants in the X-linked ETS transcription factor gene
ELF4
in multiple unrelated male patients with early onset mucosal autoinflammation and inflammatory bowel disease (IBD) characteristics, including fevers and ulcers that responded to interleukin-1 (IL-1), tumor necrosis factor or IL-12p40 blockade. Using cells from patients and newly generated mouse models, we uncovered ELF4-mutant macrophages having hyperinflammatory responses to a range of innate stimuli. In mouse macrophages, Elf4 both sustained the expression of anti-inflammatory genes, such as
Il1rn
, and limited the upregulation of inflammation amplifiers, including
S100A8
,
Lcn2
,
Trem1
and neutrophil chemoattractants. Blockade of Trem1 reversed inflammation and intestine pathology after in vivo lipopolysaccharide challenge in mice carrying patient-derived variants in Elf4. Thus, ELF4 restrains inflammation and protects against mucosal disease, a discovery with broad translational relevance for human inflammatory disorders such as IBD.
Lucas and colleagues describe loss-of-function variants in the X-linked ETS transcription factor
ELF4
in multiple unrelated male patients with early onset mucosal autoinflammation and inflammatory bowel disease (IBD)-like features.
Journal Article