Insights into Coupled Folding and Binding Mechanisms from Kinetic Studies

Intrinsically disordered proteins (IDPs) are characterised by a lack of defined structure. Since their identification more than a decade ago, many questions regarding their functional relevance and interaction mechanisms remain unanswered. While most experiments have taken equilibrium and structural perspectives, fewer studies have investigated the kinetics of their interactions. Here we review and highlight the type of information that can be gained from kinetic studies. In particular, we show how kinetic studies of coupled folding and binding reactions, an important class of signalling event, are needed to determine mechanisms.This work was supported by the Wellcome Trust (WT 095195MA). M.D.C. is supported by a BBSRC studentship; L.D. by an EPSRC studentship B.I.M.W. by the Cambridge Trust. JC is a Senior Wellcome Trust Research Fellow.This is the final version of the article. It first appeared from the American Society for Biochemistry and Molecular Biology via https://doi.org/10.1074/jbc.R115.69271

Insights into Coupled Folding and Binding Mechanisms from Kinetic Studies.

Intrinsically disordered proteins (IDPs) are characterized by a lack of persistent structure. Since their identification more than a decade ago, many questions regarding their functional relevance and interaction mechanisms remain unanswered. Although most experiments have taken equilibrium and structural perspectives, fewer studies have investigated the kinetics of their interactions. Here we review and highlight the type of information that can be gained from kinetic studies. In particular, we show how kinetic studies of coupled folding and binding reactions, an important class of signaling event, are needed to determine mechanisms.This work was supported by the Wellcome Trust (WT 095195MA). M.D.C. is supported by a BBSRC studentship; L.D. by an EPSRC studentship B.I.M.W. by the Cambridge Trust. JC is a Senior Wellcome Trust Research Fellow.This is the final version of the article. It first appeared from the American Society for Biochemistry and Molecular Biology via https://doi.org/10.1074/jbc.R115.69271

Extrinsic conditions influence the self-association and structure of IF1, the regulatory protein of mitochondrial ATP synthase.

The endogenous inhibitor of ATP synthase in mitochondria, called IF1, conserves cellular energy when the proton-motive force collapses by inhibiting ATP hydrolysis. Around neutrality, the 84-amino-acid bovine IF1 is thought to self-assemble into active dimers and, under alkaline conditions, into inactive tetramers and higher oligomers. Dimerization is mediated by formation of an antiparallel α-helical coiled-coil involving residues 44-84. The inhibitory region of each monomer from residues 1-46 is largely α-helical in crystals, but disordered in solution. The formation of the inhibited enzyme complex requires the hydrolysis of two ATP molecules, and in the complex the disordered region from residues 8-13 is extended and is followed by an α-helix from residues 14-18 and a longer α-helix from residue 21, which continues unbroken into the coiled-coil region. From residues 21-46, the long α-helix binds to other α-helices in the C-terminal region of predominantly one of the β-subunits in the most closed of the three catalytic interfaces. The definition of the factors that influence the self-association of IF1 is a key to understanding the regulation of its inhibitory properties. Therefore, we investigated the influence of pH and salt-types on the self-association of bovine IF1 and the folding of its unfolded region. We identified the equilibrium between dimers and tetramers as a potential central factor in the in vivo modulation of the inhibitory activity and suggest that the intrinsically disordered region makes its inhibitory potency exquisitely sensitive and responsive to physiological changes that influence the capability of mitochondria to make ATP

Prospectus, November 1, 1978

CELEBRATION OF WOMEN\u27S CREATIVITY\u27; letters to the editor: One student feels Tobacco chewers rate low; What is a clamato?; Corrections; Fall play coming soon; DePree to visit PC; Concert pianist gives recital at PC; PC visitation week begins this week; Italian beef sale kicks off Parkland College activities for following week; Mini-course at PC; Long Living Program hosts exercise workshop; Seminary Day starts Thursday; PC students donate 77 pints of blood in drive; Using research animals is topic of essay contest; Hottest band in the galaxy left crowd cold; Pop Quiz!; Louise Parker is valuable asset to Parkland students and faculty; Task force to be made for competency testing; \u27Celebration of Women\u27s Creativity\u27; Ron Taylor is Parkland\u27s new advertising instructor; Conference for horse owners Nov. 18-19; Children have different ideas about religion; Learning Lab helps students nurses study; Evolution-- Are the apes laughing at us?; Only \u27the tip of the iceberg\u27 is encountered by W.A.R.; New cases opened by Women Against Rape; Weekly events for Krannert; Switchboard for women added; Classifieds; WPCD Top 20 for the Week of Oct. 30; Baseball season has ended, now looking to next year; Henry is new treasurer; Cobras defeat Lincoln Land; Parkland College to host the National cross country meet; Elam, Larson, lead X-country to 5th in state; Fast Freddy Contest; Freddy causes problems but wants to be tougherhttps://spark.parkland.edu/prospectus_1978/1005/thumbnail.jp

Prospectus, April 19, 1977

BEWARE! IDIOTS COMING THURSDAY; Stu-Go gets together, discusses student adv.; Have you Petitioned? Graduation set May 22; Dodds, Miller: Board seats incumbents; Senior citizens exhibit arts and crafts crafts; Letters to the editor: Administrators, wise up!; Staff editorial: Culture ignores death; Stu-Go petitions due; Artist in residence: Dancer to be at PC; Food Service bidding opened until April 29; Veterans Awareness Week calls for vet. button wearers; Millikin offers vis. day; SSU offers com. college grad. program; Speed up process: Computers to be used for registration; Film festival this week; An interview: It\u27s a challenge: Dye; \u27After he ate them, he exploded\u27: Authors of Merit: Tales of Woo and Nygoed; Brahms\u27 Opus 45: Requiem tells sorrow; Stage review: \u27Under Milk Wood\u27 is charming but too fast; Mediasceen: TV contest is offered; Classifieds; Sprint medley third in Cobra\u27s strong showing; Final Exam Schedule: Spring Semester, 1976-1977; Women\u27s softball team meets Lincoln Land today at 4:00; Seven-hitter: Cobras sweep doubleheader; Oscar Lambdin: Sangamon State signs \u27Mr. Intramural\u27https://spark.parkland.edu/prospectus_1977/1019/thumbnail.jp

Delivery of an Ebola Virus-Positive Stillborn Infant in a Rural Community Health Center, Sierra Leone, 2015.

We report the case of an Ebola virus (EBOV) RNA-negative pregnant woman who delivered an EBOV RNA-positive stillborn infant at a community health center in rural Sierra Leone, 1 month after the mother's last possible exposure. The mother was later found to be immunoglobulins M and G positive indicating previous infection. The apparent absence of Ebola symptoms and not recognizing that the woman had previous contact with an Ebola patient led health workers performing the delivery to wear only minimal personal protection, potentially exposing them to a high risk of EBOV infection. This case emphasizes the importance of screening for epidemiological risk factors as well as classic and atypical symptoms of Ebola when caring for pregnant women, even once they have passed the typical time frame for exposure and incubation expected in nonpregnant adults. It also illustrates the need for health-care workers to use appropriate personal protection equipment when caring for pregnant women in an Ebola setting

Diverse Profiles of Anxiety Related Disorders in Fragile X, Cornelia de Lange and Rubinstein–Taybi Syndromes

Anxiety disorders are heightened in specific genetic syndromes in comparison to intellectual disability of heterogeneous aetiology. In this study, we described and contrasted anxiety symptomatology in fragile X (FXS), Cornelia de Lange (CdLS) and Rubinstein–Taybi syndromes (RTS), and compared the symptomatology to normative data for typically-developing children and children diagnosed with an anxiety disorder. Scores did not differ between children diagnosed with an anxiety disorder and (a) participants with FXS on social phobia, panic/agoraphobia, physical injury fears, and obsessive–compulsive subscales (b) participants with CdLS on separation anxiety, generalized anxiety, panic/agoraphobia, physical injury fears and obsessive–compulsive subscales, and (c) participants with RTS on panic/agoraphobia and obsessive–compulsive subscales. The results highlight divergent profiles of anxiety symptomatology between these groups

Ebola virus epidemiology, transmission, and evolution during seven months in Sierra Leone

The 2013-2015 Ebola virus disease (EVD) epidemic is caused by the Makona variant of Ebola virus (EBOV). Early in the epidemic, genome sequencing provided insights into virus evolution and transmission and offered important information for outbreak response. Here, we analyze sequences from 232 patients sampled over 7 months in Sierra Leone, along with 86 previously released genomes from earlier in the epidemic. We confirm sustained human-to-human transmission within Sierra Leone and find no evidence for import or export of EBOV across national borders after its initial introduction. Using high-depth replicate sequencing, we observe both host-to-host transmission and recurrent emergence of intrahost genetic variants. We trace the increasing impact of purifying selection in suppressing the accumulation of nonsynonymous mutations over time. Finally, we note changes in the mucin-like domain of EBOV glycoprotein that merit further investigation. These findings clarify the movement of EBOV within the region and describe viral evolution during prolonged human-to-human transmission

European Position Paper on Rhinosinusitis and Nasal Polyps 2020

The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012. The core objective of the EPOS2020 guideline is to provide revised, up-to-date and clear evidence-based recommendations and integrated care pathways in ARS and CRS. EPOS2020 provides an update on the literature published and studies undertaken in the eight years since the EPOS2012 position paper was published and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery. EPOS2020 also involves new stakeholders, including pharmacists and patients, and addresses new target users who have become more involved in the management and treatment of rhinosinusitis since the publication of the last EPOS document, including pharmacists, nurses, specialised care givers and indeed patients themselves, who employ increasing self-management of their condition using over the counter treatments. The document provides suggestions for future research in this area and offers updated guidance for definitions and outcome measurements in research in different settings. EPOS2020 contains chapters on definitions and classification where we have defined a large number of terms and indicated preferred terms. A new classification of CRS into primary and secondary CRS and further division into localized and diffuse disease, based on anatomic distribution is proposed. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, allergic rhinitis, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. All available evidence for the management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is systematically reviewed and integrated care pathways based on the evidence are proposed. Despite considerable increases in the amount of quality publications in recent years, a large number of practical clinical questions remain. It was agreed that the best way to address these was to conduct a Delphi exercise. The results have been integrated into the respective sections. Last but not least, advice for patients and pharmacists and a new list of research needs are included.Peer reviewe