A helical structural nucleus is the primary elongating unit of insulin amyloid fibrils.

Abstract:

:Although amyloid fibrillation is generally believed to be a nucleation-dependent process, the nuclei are largely structurally uncharacterized. This is in part due to the inherent experimental challenge associated with structural descriptions of individual components in a dynamic multi-component equilibrium. There are indications that oligomeric aggregated precursors of fibrillation, and not mature fibrils, are the main cause of cytotoxicity in amyloid disease. This further emphasizes the importance of characterizing early fibrillation events. Here we present a kinetic x-ray solution scattering study of insulin fibrillation, revealing three major components: insulin monomers, mature fibrils, and an oligomeric species. Low-resolution three-dimensional structures are determined for the fibril repeating unit and for the oligomer, the latter being a helical unit composed of five to six insulin monomers. This helical oligomer is likely to be a structural nucleus, which accumulates above the supercritical concentration used in our experiments. The growth rate of the fibrils is proportional to the amount of the helical oligomer present in solution, suggesting that these oligomers elongate the fibrils. Hence, the structural nucleus and elongating unit in insulin amyloid fibrillation may be the same structural component above supercritical concentrations. A novel elongation pathway of insulin amyloid fibrils is proposed, based on the shape and size of the fibrillation precursor. The distinct helical oligomer described in this study defines a conceptually new basis of structure-based drug design against amyloid diseases.

journal_name

PLoS Biol

journal_title

PLoS biology

authors

Vestergaard B,Groenning M,Roessle M,Kastrup JS,van de Weert M,Flink JM,Frokjaer S,Gajhede M,Svergun DI

doi

10.1371/journal.pbio.0050134

subject

Has Abstract

pub_date

2007-05-01 00:00:00

pages

e134

issue

5

eissn

1544-9173

issn

1545-7885

pii

06-PLBI-RA-1795R3

journal_volume

5

pub_type

杂志文章
  • Hox proteins display a common and ancestral ability to diversify their interaction mode with the PBC class cofactors.

    abstract::Hox transcription factors control a number of developmental processes with the help of the PBC class proteins. In vitro analyses have established that the formation of Hox/PBC complexes relies on a short conserved Hox protein motif called the hexapeptide (HX). This paradigm is at the basis of the vast majority of expe...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.1001351

    authors: Hudry B,Remacle S,Delfini MC,Rezsohazy R,Graba Y,Merabet S

    更新日期:2012-01-01 00:00:00

  • Activity patterns in mammals: Circadian dominance challenged.

    abstract::The evidence that diel patterns of physiology and behaviour in mammals are governed by circadian 'clocks' is based almost entirely on studies of nocturnal rodents. The emergent circadian paradigm, however, neglects the roles of energy metabolism and alimentary function (feeding and digestion) as determinants of activi...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.3000360

    authors: Hazlerigg DG,Tyler NJC

    更新日期:2019-07-15 00:00:00

  • Reply to "Far away from the lamppost".

    abstract::In this Formal Comment, the authors of the recent publication "Large-scale investigation of the reasons why potentially important genes are ignored" maintain that it can be read as an opportunity to explore the unknown. ...

    journal_title:PLoS biology

    pub_type: 评论,杂志文章

    doi:10.1371/journal.pbio.3000075

    authors: Stoeger T,Gerlach M,Morimoto RI,Amaral LAN

    更新日期:2018-12-11 00:00:00

  • Promotion of reprogramming to ground state pluripotency by signal inhibition.

    abstract::Induced pluripotent stem (iPS) cells are generated from somatic cells by genetic manipulation. Reprogramming entails multiple transgene integrations and occurs apparently stochastically in rare cells over many days. Tissue stem cells may be subject to less-stringent epigenetic restrictions than other cells and might t...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.0060253

    authors: Silva J,Barrandon O,Nichols J,Kawaguchi J,Theunissen TW,Smith A

    更新日期:2008-10-21 00:00:00

  • Laws of concatenated perception: Vision goes for novelty, decisions for perseverance.

    abstract::Every instant of perception depends on a cascade of brain processes calibrated to the history of sensory and decisional events. In the present work, we show that human visual perception is constantly shaped by two contrasting forces exerted by sensory adaptation and past decisions. In a series of experiments, we used ...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.3000144

    authors: Pascucci D,Mancuso G,Santandrea E,Della Libera C,Plomp G,Chelazzi L

    更新日期:2019-03-05 00:00:00

  • Anything you can do, you can do better: neural substrates of incentive-based performance enhancement.

    abstract::Performance-based pay schemes in many organizations share the fundamental assumption that the performance level for a given task will increase as a function of the amount of incentive provided. Consistent with this notion, psychological studies have demonstrated that expectations of reward can improve performance on a...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.1001272

    authors: Liljeholm M,O'Doherty JP

    更新日期:2012-02-01 00:00:00

  • Evolthon: A community endeavor to evolve lab evolution.

    abstract::In experimental evolution, scientists evolve organisms in the lab, typically by challenging them to new environmental conditions. How best to evolve a desired trait? Should the challenge be applied abruptly, gradually, periodically, sporadically? Should one apply chemical mutagenesis, and do strains with high innate m...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.3000182

    authors: Kaminski Strauss S,Schirman D,Jona G,Brooks AN,Kunjapur AM,Nguyen Ba AN,Flint A,Solt A,Mershin A,Dixit A,Yona AH,Csörgő B,Busby BP,Hennig BP,Pál C,Schraivogel D,Schultz D,Wernick DG,Agashe D,Levi D,Zabezhinsky D,

    更新日期:2019-03-29 00:00:00

  • Networking in the Plant Microbiome.

    abstract::Almost all higher organisms, including plants, insects, and mammals, are colonized by complex microbial communities and harbor a microbiome. Emerging studies with plants reveal that these microbiomes are structured and form complex, interconnected microbial networks. Within these networks, different taxa have differen...

    journal_title:PLoS biology

    pub_type: 评论,杂志文章

    doi:10.1371/journal.pbio.1002378

    authors: van der Heijden MG,Hartmann M

    更新日期:2016-02-12 00:00:00

  • Do plants have a segregated germline?

    abstract::For the last 100 years, it has been uncontroversial to state that the plant germline is set aside late in development, but there is surprisingly little evidence to support this view. In contrast, much evolutionary theory and several recent empirical studies seem to suggest the opposite-that the germlines of some and p...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.2005439

    authors: Lanfear R

    更新日期:2018-05-16 00:00:00

  • Neural activity during a simple reaching task in macaques is counter to gating and rebound in basal ganglia-thalamic communication.

    abstract::Task-related activity in the ventral thalamus, a major target of basal ganglia output, is often assumed to be permitted or triggered by changes in basal ganglia activity through gating- or rebound-like mechanisms. To test those hypotheses, we sampled single-unit activity from connected basal ganglia output and thalami...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.3000829

    authors: Schwab BC,Kase D,Zimnik A,Rosenbaum R,Codianni MG,Rubin JE,Turner RS

    更新日期:2020-10-13 00:00:00

  • Insulin and mTOR Pathway Regulate HDAC3-Mediated Deacetylation and Activation of PGK1.

    abstract::Phosphoglycerate kinase 1 (PGK1) catalyzes the reversible transfer of a phosphoryl group from 1, 3-bisphosphoglycerate (1, 3-BPG) to ADP, producing 3-phosphoglycerate (3-PG) and ATP. PGK1 plays a key role in coordinating glycolytic energy production with one-carbon metabolism, serine biosynthesis, and cellular redox r...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.1002243

    authors: Wang S,Jiang B,Zhang T,Liu L,Wang Y,Wang Y,Chen X,Lin H,Zhou L,Xia Y,Chen L,Yang C,Xiong Y,Ye D,Guan KL

    更新日期:2015-09-10 00:00:00

  • ELF5 Drives Lung Metastasis in Luminal Breast Cancer through Recruitment of Gr1+ CD11b+ Myeloid-Derived Suppressor Cells.

    abstract::During pregnancy, the ETS transcription factor ELF5 establishes the milk-secreting alveolar cell lineage by driving a cell fate decision of the mammary luminal progenitor cell. In breast cancer, ELF5 is a key transcriptional determinant of tumor subtype and has been implicated in the development of insensitivity to an...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.1002330

    authors: Gallego-Ortega D,Ledger A,Roden DL,Law AM,Magenau A,Kikhtyak Z,Cho C,Allerdice SL,Lee HJ,Valdes-Mora F,Herrmann D,Salomon R,Young AI,Lee BY,Sergio CM,Kaplan W,Piggin C,Conway JR,Rabinovich B,Millar EK,Oakes SR,C

    更新日期:2015-12-30 00:00:00

  • The DEAD-box Protein Rok1 Orchestrates 40S and 60S Ribosome Assembly by Promoting the Release of Rrp5 from Pre-40S Ribosomes to Allow for 60S Maturation.

    abstract::DEAD-box proteins are ubiquitous regulators of RNA biology. While commonly dubbed "helicases," their activities also include duplex annealing, adenosine triphosphate (ATP)-dependent RNA binding, and RNA-protein complex remodeling. Rok1, an essential DEAD-box protein, and its cofactor Rrp5 are required for ribosome ass...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.1002480

    authors: Khoshnevis S,Askenasy I,Johnson MC,Dattolo MD,Young-Erdos CL,Stroupe ME,Karbstein K

    更新日期:2016-06-09 00:00:00

  • The taste of ribonucleosides: Novel macronutrients essential for larval growth are sensed by Drosophila gustatory receptor proteins.

    abstract::Animals employ various types of taste receptors to identify and discriminate between different nutritious food chemicals. These macronutrients are thought to fall into 3 major groups: carbohydrates/sugars, proteins/amino acids, and fats. Here, we report that Drosophila larvae exhibit a novel appetitive feeding behavio...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.2005570

    authors: Mishra D,Thorne N,Miyamoto C,Jagge C,Amrein H

    更新日期:2018-08-07 00:00:00

  • Correction: Regulating toxic chemicals for public and environmental health.

    abstract::[This corrects the article DOI: 10.1371/journal.pbio.2004814.]. ...

    journal_title:PLoS biology

    pub_type: 杂志文章,已发布勘误

    doi:10.1371/journal.pbio.1002619

    authors: PLOS Biology Staff.

    更新日期:2018-01-25 00:00:00

  • Regulation of mammary stem/progenitor cells by PTEN/Akt/beta-catenin signaling.

    abstract::Recent evidence suggests that many malignancies, including breast cancer, are driven by a cellular subcomponent that displays stem cell-like properties. The protein phosphatase and tensin homolog (PTEN) is inactivated in a wide range of human cancers, an alteration that is associated with a poor prognosis. Because PTE...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.1000121

    authors: Korkaya H,Paulson A,Charafe-Jauffret E,Ginestier C,Brown M,Dutcher J,Clouthier SG,Wicha MS

    更新日期:2009-06-02 00:00:00

  • CDKN1B/p27 is localized in mitochondria and improves respiration-dependent processes in the cardiovascular system-New mode of action for caffeine.

    abstract::We show that the cyclin-dependent kinase inhibitor 1B (CDKN1B)/p27, previously known as a cell cycle inhibitor, is also localized within mitochondria. The migratory capacity of endothelial cells, which need intact mitochondria, is completely dependent on mitochondrial p27. Mitochondrial p27 improves mitochondrial memb...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.2004408

    authors: Ale-Agha N,Goy C,Jakobs P,Spyridopoulos I,Gonnissen S,Dyballa-Rukes N,Aufenvenne K,von Ameln F,Zurek M,Spannbrucker T,Eckermann O,Jakob S,Gorressen S,Abrams M,Grandoch M,Fischer JW,Köhrer K,Deenen R,Unfried K,Altsch

    更新日期:2018-06-21 00:00:00

  • Ammonium toxicity and potassium limitation in yeast.

    abstract::DNA microarray analysis of gene expression in steady-state chemostat cultures limited for potassium revealed a surprising connection between potassium and ammonium: potassium limits growth only when ammonium is the nitrogen source. Under potassium limitation, ammonium appears to be toxic for Saccharomyces cerevisiae. ...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.0040351

    authors: Hess DC,Lu W,Rabinowitz JD,Botstein D

    更新日期:2006-10-01 00:00:00

  • Ionotropic Chemosensory Receptors Mediate the Taste and Smell of Polyamines.

    abstract::The ability to find and consume nutrient-rich diets for successful reproduction and survival is fundamental to animal life. Among the nutrients important for all animals are polyamines, a class of pungent smelling compounds required in numerous cellular and organismic processes. Polyamine deficiency or excess has detr...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.1002454

    authors: Hussain A,Zhang M,Üçpunar HK,Svensson T,Quillery E,Gompel N,Ignell R,Grunwald Kadow IC

    更新日期:2016-05-04 00:00:00

  • A question of fate.

    abstract::Ever since the discovery of neural stem cells in the mammalian brain, the possibility of brain tissue regeneration has captured the minds of scientists, clinicians, and the public. Neural stem cells have been envisioned as a source of donor cells for transplantation and vectors for the delivery of gene therapy. Over t...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.2002329

    authors: Maletic-Savatic M

    更新日期:2017-05-15 00:00:00

  • Cryptochrome mediates light-dependent magnetosensitivity of Drosophila's circadian clock.

    abstract::Since 1960, magnetic fields have been discussed as Zeitgebers for circadian clocks, but the mechanism by which clocks perceive and process magnetic information has remained unknown. Recently, the radical-pair model involving light-activated photoreceptors as magnetic field sensors has gained considerable support, and ...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.1000086

    authors: Yoshii T,Ahmad M,Helfrich-Förster C

    更新日期:2009-04-07 00:00:00

  • Structure of the DP1-DP2 PolD complex bound with DNA and its implications for the evolutionary history of DNA and RNA polymerases.

    abstract::PolD is an archaeal replicative DNA polymerase (DNAP) made of a proofreading exonuclease subunit (DP1) and a larger polymerase catalytic subunit (DP2). Recently, we reported the individual crystal structures of the DP1 and DP2 catalytic cores, thereby revealing that PolD is an atypical DNAP that has all functional pro...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.3000122

    authors: Raia P,Carroni M,Henry E,Pehau-Arnaudet G,Brûlé S,Béguin P,Henneke G,Lindahl E,Delarue M,Sauguet L

    更新日期:2019-01-18 00:00:00

  • Proteome-wide identification of HSP70/HSC70 chaperone clients in human cells.

    abstract::The 70 kDa heat shock protein (HSP70) family of chaperones are the front line of protection from stress-induced misfolding and aggregation of polypeptides in most organisms and are responsible for promoting the stability, folding, and degradation of clients to maintain cellular protein homeostasis. Here, we demonstrat...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.3000606

    authors: Ryu SW,Stewart R,Pectol DC,Ender NA,Wimalarathne O,Lee JH,Zanini CP,Harvey A,Huibregtse JM,Mueller P,Paull TT

    更新日期:2020-07-20 00:00:00

  • The credibility crisis in research: Can economics tools help?

    abstract::The issue of nonreplicable evidence has attracted considerable attention across biomedical and other sciences. This concern is accompanied by an increasing interest in reforming research incentives and practices. How to optimally perform these reforms is a scientific problem in itself, and economics has several scient...

    journal_title:PLoS biology

    pub_type: 杂志文章,评审

    doi:10.1371/journal.pbio.2001846

    authors: Gall T,Ioannidis JPA,Maniadis Z

    更新日期:2017-04-26 00:00:00

  • Heterochromatin delays CRISPR-Cas9 mutagenesis but does not influence the outcome of mutagenic DNA repair.

    abstract::Genome editing occurs in the context of chromatin, which is heterogeneous in structure and function across the genome. Chromatin heterogeneity is thought to affect genome editing efficiency, but this has been challenging to quantify due to the presence of confounding variables. Here, we develop a method that exploits ...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.2005595

    authors: Kallimasioti-Pazi EM,Thelakkad Chathoth K,Taylor GC,Meynert A,Ballinger T,Kelder MJE,Lalevée S,Sanli I,Feil R,Wood AJ

    更新日期:2018-12-12 00:00:00

  • Correction: Song playbacks demonstrate slower evolution of song discrimination in birds from Amazonia than from temperate North America.

    abstract::[This corrects the article DOI: 10.1371/journal.pbio.3000478.]. ...

    journal_title:PLoS biology

    pub_type: 已发布勘误

    doi:10.1371/journal.pbio.3000568

    authors: PLOS Biology Staff.

    更新日期:2019-11-13 00:00:00

  • A signaling protease required for melanization in Drosophila affects resistance and tolerance of infections.

    abstract::Organisms evolve two routes to surviving infections-they can resist pathogen growth (resistance) and they can endure the pathogenesis of infection (tolerance). The sum of these two properties together defines the defensive capabilities of the host. Typically, studies of animal defenses focus on either understanding re...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.0060305

    authors: Ayres JS,Schneider DS

    更新日期:2008-12-09 00:00:00

  • Some agreement on kin selection and eusociality?

    abstract::The authors of "Relatedness, Conflict, and the Evolution of Eusociality" respond to objections raised by Martin Nowak and Benjamin Allen. ...

    journal_title:PLoS biology

    pub_type: 评论,杂志文章

    doi:10.1371/journal.pbio.1002133

    authors: Queller DC,Rong S,Liao X

    更新日期:2015-04-24 00:00:00

  • Polarised asymmetric inheritance of accumulated protein damage in higher eukaryotes.

    abstract::Disease-associated misfolded proteins or proteins damaged due to cellular stress are generally disposed via the cellular protein quality-control system. However, under saturating conditions, misfolded proteins will aggregate. In higher eukaryotes, these aggregates can be transported to accumulate in aggresomes at the ...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.0040417

    authors: Rujano MA,Bosveld F,Salomons FA,Dijk F,van Waarde MA,van der Want JJ,de Vos RA,Brunt ER,Sibon OC,Kampinga HH

    更新日期:2006-12-01 00:00:00

  • Unique 5'-P recognition and basis for dG:dGTP misincorporation of ASFV DNA polymerase X.

    abstract::African swine fever virus (ASFV) can cause highly lethal disease in pigs and is becoming a global threat. ASFV DNA Polymerase X (AsfvPolX) is the most distinctive DNA polymerase identified to date; it lacks two DNA-binding domains (the thumb domain and 8-KD domain) conserved in the homologous proteins. AsfvPolX cataly...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.1002599

    authors: Chen Y,Zhang J,Liu H,Gao Y,Li X,Zheng L,Cui R,Yao Q,Rong L,Li J,Huang Z,Ma J,Gan J

    更新日期:2017-02-28 00:00:00