Time-resolved studies define the nature of toxic IAPP intermediates, providing insight for anti-amyloidosis therapeutics.

Abstract:

:Islet amyloidosis by IAPP contributes to pancreatic β-cell death in diabetes, but the nature of toxic IAPP species remains elusive. Using concurrent time-resolved biophysical and biological measurements, we define the toxic species produced during IAPP amyloid formation and link their properties to induction of rat INS-1 β-cell and murine islet toxicity. These globally flexible, low order oligomers upregulate pro-inflammatory markers and induce reactive oxygen species. They do not bind 1-anilnonaphthalene-8-sulphonic acid and lack extensive β-sheet structure. Aromatic interactions modulate, but are not required for toxicity. Not all IAPP oligomers are toxic; toxicity depends on their partially structured conformational states. Some anti-amyloid agents paradoxically prolong cytotoxicity by prolonging the lifetime of the toxic species. The data highlight the distinguishing properties of toxic IAPP oligomers and the common features that they share with toxic species reported for other amyloidogenic polypeptides, providing information for rational drug design to treat IAPP induced β-cell death.

journal_name

Elife

journal_title

eLife

authors

Abedini A,Plesner A,Cao P,Ridgway Z,Zhang J,Tu LH,Middleton CT,Chao B,Sartori DJ,Meng F,Wang H,Wong AG,Zanni MT,Verchere CB,Raleigh DP,Schmidt AM

doi

10.7554/eLife.12977

subject

Has Abstract

pub_date

2016-05-23 00:00:00

issn

2050-084X

journal_volume

5

pub_type

杂志文章

相关文献

eLife文献大全
  • HRI coordinates translation necessary for protein homeostasis and mitochondrial function in erythropoiesis.

    abstract::Iron and heme play central roles in the production of red blood cells, but the underlying mechanisms remain incompletely understood. Heme-regulated eIF2α kinase (HRI) controls translation by phosphorylating eIF2α. Here, we investigate the global impact of iron, heme, and HRI on protein translation in vivo in murine pr...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.46976

    authors: Zhang S,Macias-Garcia A,Ulirsch JC,Velazquez J,Butty VL,Levine SS,Sankaran VG,Chen JJ

    更新日期:2019-04-29 00:00:00

  • Importance of miRNA stability and alternative primary miRNA isoforms in gene regulation during Drosophila development.

    abstract::Mature microRNAs (miRNAs) are processed from primary transcripts (pri-miRNAs), and their expression is controlled at transcriptional and post-transcriptional levels. However, how regulation at multiple levels achieves precise control remains elusive. Using published and new datasets, we profile a time course of mature...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.38389

    authors: Zhou L,Lim MYT,Kaur P,Saj A,Bortolamiol-Becet D,Gopal V,Tolwinski N,Tucker-Kellogg G,Okamura K

    更新日期:2018-07-19 00:00:00

  • An extended retinotopic map of mouse cortex.

    abstract::Visual perception and behavior are mediated by cortical areas that have been distinguished using architectonic and retinotopic criteria. We employed fluorescence imaging and GCaMP6 reporter mice to generate retinotopic maps, revealing additional regions of retinotopic organization that extend into barrel and retrosple...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.18372

    authors: Zhuang J,Ng L,Williams D,Valley M,Li Y,Garrett M,Waters J

    更新日期:2017-01-06 00:00:00

  • Multisite dependency of an E3 ligase controls monoubiquitylation-dependent cell fate decisions.

    abstract::Metazoan development depends on tightly regulated gene expression programs that instruct progenitor cells to adopt specialized fates. Recent work found that posttranslational modifications, such as monoubiquitylation, can determine cell fate also independently of effects on transcription, yet how monoubiquitylation is...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.35407

    authors: Werner A,Baur R,Teerikorpi N,Kaya DU,Rape M

    更新日期:2018-07-12 00:00:00

  • Mechanisms of nucleotide selection by telomerase.

    abstract::Telomerase extends telomere sequences at chromosomal ends to protect genomic DNA. During this process it must select the correct nucleotide from a pool of nucleotides with various sugars and base pairing properties, which is critically important for the proper capping of telomeric sequences by shelterin. Unfortunately...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.55438

    authors: Schaich MA,Sanford SL,Welfer GA,Johnson SA,Khoang TH,Opresko PL,Freudenthal BD

    更新日期:2020-06-05 00:00:00

  • The ribosomal protein Asc1/RACK1 is required for efficient translation of short mRNAs.

    abstract::Translation is a core cellular process carried out by a highly conserved macromolecular machine, the ribosome. There has been remarkable evolutionary adaptation of this machine through the addition of eukaryote-specific ribosomal proteins whose individual effects on ribosome function are largely unknown. Here we show ...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.11154

    authors: Thompson MK,Rojas-Duran MF,Gangaramani P,Gilbert WV

    更新日期:2016-04-27 00:00:00

  • KRAS-dependent sorting of miRNA to exosomes.

    abstract::Mutant KRAS colorectal cancer (CRC) cells release protein-laden exosomes that can alter the tumor microenvironment. To test whether exosomal RNAs also contribute to changes in gene expression in recipient cells, and whether mutant KRAS might regulate the composition of secreted microRNAs (miRNAs), we compared small RN...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.07197

    authors: Cha DJ,Franklin JL,Dou Y,Liu Q,Higginbotham JN,Demory Beckler M,Weaver AM,Vickers K,Prasad N,Levy S,Zhang B,Coffey RJ,Patton JG

    更新日期:2015-07-01 00:00:00

  • Inhibition by small-molecule ligands of formation of amyloid fibrils of an immunoglobulin light chain variable domain.

    abstract::Overproduction of immunoglobulin light chains leads to systemic amyloidosis, a lethal disease characterized by the formation of amyloid fibrils in patients' tissues. Excess light chains are in equilibrium between dimers and less stable monomers which can undergo irreversible aggregation to the amyloid state. The dimer...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.10935

    authors: Brumshtein B,Esswein SR,Salwinski L,Phillips ML,Ly AT,Cascio D,Sawaya MR,Eisenberg DS

    更新日期:2015-11-18 00:00:00

  • Cytokinesis in vertebrate cells initiates by contraction of an equatorial actomyosin network composed of randomly oriented filaments.

    abstract::The actomyosin ring generates force to ingress the cytokinetic cleavage furrow in animal cells, yet its filament organization and the mechanism of contractility is not well understood. We quantified actin filament order in human cells using fluorescence polarization microscopy and found that cleavage furrow ingression...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.30867

    authors: Spira F,Cuylen-Haering S,Mehta S,Samwer M,Reversat A,Verma A,Oldenbourg R,Sixt M,Gerlich DW

    更新日期:2017-11-06 00:00:00

  • Symmetry broken and rebroken during the ATP hydrolysis cycle of the mitochondrial Hsp90 TRAP1.

    abstract::Hsp90 is a homodimeric ATP-dependent molecular chaperone that remodels its substrate 'client' proteins, facilitating their folding and activating them for biological function. Despite decades of research, the mechanism connecting ATP hydrolysis and chaperone function remains elusive. Particularly puzzling has been the...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.25235

    authors: Elnatan D,Betegon M,Liu Y,Ramelot T,Kennedy MA,Agard DA

    更新日期:2017-07-25 00:00:00

  • The distribution of fitness effects among synonymous mutations in a gene under directional selection.

    abstract::The fitness effects of synonymous mutations, nucleotide changes that do not alter the encoded amino acid, have often been assumed to be neutral, but a growing body of evidence suggests otherwise. We used site-directed mutagenesis coupled with direct measures of competitive fitness to estimate the distribution of fitne...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.45952

    authors: Lebeuf-Taylor E,McCloskey N,Bailey SF,Hinz A,Kassen R

    更新日期:2019-07-19 00:00:00

  • Family matters.

    abstract::Genome sequence data from a range of animal species are raising questions about the origins of glutamate receptors. ...

    journal_title:eLife

    pub_type: 评论,杂志文章

    doi:10.7554/eLife.43815

    authors: Mayer ML,Jegla T

    更新日期:2018-12-28 00:00:00

  • Tumor initiating cells induce Cxcr4-mediated infiltration of pro-tumoral macrophages into the brain.

    abstract::It is now clear that microglia and macrophages are present in brain tumors, but whether or how they affect initiation and development of tumors is not known. Exploiting the advantages of the zebrafish (Danio rerio) model, we showed that macrophages and microglia respond immediately upon oncogene activation in the brai...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.31918

    authors: Chia K,Mazzolini J,Mione M,Sieger D

    更新日期:2018-02-21 00:00:00

  • An essential Staphylococcus aureus cell division protein directly regulates FtsZ dynamics.

    abstract::Binary fission has been well studied in rod-shaped bacteria, but the mechanisms underlying cell division in spherical bacteria are poorly understood. Rod-shaped bacteria harbor regulatory proteins that place and remodel the division machinery during cytokinesis. In the spherical human pathogen Staphylococcus aureus, w...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.38856

    authors: Eswara PJ,Brzozowski RS,Viola MG,Graham G,Spanoudis C,Trebino C,Jha J,Aubee JI,Thompson KM,Camberg JL,Ramamurthi KS

    更新日期:2018-10-02 00:00:00

  • Individual crop loads provide local control for collective food intake in ant colonies.

    abstract::Nutritional regulation by ants emerges from a distributed process: food is collected by a small fraction of workers, stored within the crops of individuals, and spread via local ant-to-ant interactions. The precise individual-level underpinnings of this collective regulation have remained unclear mainly due to difficu...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.31730

    authors: Greenwald EE,Baltiansky L,Feinerman O

    更新日期:2018-03-06 00:00:00

  • C. elegans neurons have functional dendritic spines.

    abstract::Dendritic spines are specialized postsynaptic structures that transduce presynaptic signals, are regulated by neural activity and correlated with learning and memory. Most studies of spine function have focused on the mammalian nervous system. However, spine-like protrusions have been reported in C. elegans (Philbrook...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.47918

    authors: Cuentas-Condori A,Mulcahy B,He S,Palumbos S,Zhen M,Miller DM 3rd

    更新日期:2019-10-04 00:00:00

  • BUB-1 promotes amphitelic chromosome biorientation via multiple activities at the kinetochore.

    abstract::Accurate chromosome segregation relies on bioriented amphitelic attachments of chromosomes to microtubules of the mitotic spindle, in which sister chromatids are connected to opposite spindle poles. BUB-1 is a protein of the Spindle Assembly Checkpoint (SAC) that coordinates chromosome attachment with anaphase onset. ...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.40690

    authors: Edwards F,Maton G,Gareil N,Canman JC,Dumont J

    更新日期:2018-12-14 00:00:00

  • The angiopoietin-like protein ANGPTL4 catalyzes unfolding of the hydrolase domain in lipoprotein lipase and the endothelial membrane protein GPIHBP1 counteracts this unfolding.

    abstract::Lipoprotein lipase (LPL) undergoes spontaneous inactivation via global unfolding and this unfolding is prevented by GPIHBP1 (Mysling et al., 2016). We now show: (1) that ANGPTL4 inactivates LPL by catalyzing the unfolding of its hydrolase domain; (2) that binding to GPIHBP1 renders LPL largely refractory to this inhib...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.20958

    authors: Mysling S,Kristensen KK,Larsson M,Kovrov O,Bensadouen A,Jørgensen TJ,Olivecrona G,Young SG,Ploug M

    更新日期:2016-12-08 00:00:00

  • Registered report: Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases.

    abstract::The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.07420

    authors: Evans B,Griner E,Reproducibility Project: Cancer Biology.

    更新日期:2015-07-31 00:00:00

  • PrkA controls peptidoglycan biosynthesis through the essential phosphorylation of ReoM.

    abstract::Peptidoglycan (PG) is the main component of bacterial cell walls and the target for many antibiotics. PG biosynthesis is tightly coordinated with cell wall growth and turnover, and many of these control activities depend upon PASTA-domain containing eukaryotic-like serine/threonine protein kinases (PASTA-eSTK) that se...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.56048

    authors: Wamp S,Rutter ZJ,Rismondo J,Jennings CE,Möller L,Lewis RJ,Halbedel S

    更新日期:2020-05-29 00:00:00

  • Functional heterogeneity within the rodent lateral orbitofrontal cortex dissociates outcome devaluation and reversal learning deficits.

    abstract::The orbitofrontal cortex (OFC) is critical for updating reward-directed behaviours flexibly when outcomes are devalued or when task contingencies are reversed. Failure to update behaviour in outcome devaluation and reversal learning procedures are considered canonical deficits following OFC lesions in non-human primat...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.37357

    authors: Panayi MC,Killcross S

    更新日期:2018-07-25 00:00:00

  • Trifunctional cross-linker for mapping protein-protein interaction networks and comparing protein conformational states.

    abstract::To improve chemical cross-linking of proteins coupled with mass spectrometry (CXMS), we developed a lysine-targeted enrichable cross-linker containing a biotin tag for affinity purification, a chemical cleavage site to separate cross-linked peptides away from biotin after enrichment, and a spacer arm that can be label...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.12509

    authors: Tan D,Li Q,Zhang MJ,Liu C,Ma C,Zhang P,Ding YH,Fan SB,Tao L,Yang B,Li X,Ma S,Liu J,Feng B,Liu X,Wang HW,He SM,Gao N,Ye K,Dong MQ,Lei X

    更新日期:2016-03-08 00:00:00

  • Correction: Salt-inducible kinase 3 regulates the mammalian circadian clock by destabilizing PER2 protein.

    abstract:: ...

    journal_title:eLife

    pub_type: 已发布勘误

    doi:10.7554/eLife.66683

    authors: Hayasaka N,Hirano A,Miyoshi Y,Tokuda IT,Yoshitane H,Matsuda J,Fukada Y

    更新日期:2021-01-25 00:00:00

  • Prolonged cross-bridge binding triggers muscle dysfunction in a Drosophila model of myosin-based hypertrophic cardiomyopathy.

    abstract::K146N is a dominant mutation in human β-cardiac myosin heavy chain, which causes hypertrophic cardiomyopathy. We examined how Drosophila muscle responds to this mutation and integratively analyzed the biochemical, physiological and mechanical foundations of the disease. ATPase assays, actin motility, and indirect flig...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.38064

    authors: Kronert WA,Bell KM,Viswanathan MC,Melkani GC,Trujillo AS,Huang A,Melkani A,Cammarato A,Swank DM,Bernstein SI

    更新日期:2018-08-13 00:00:00

  • Acetylcholine is released in the basolateral amygdala in response to predictors of reward and enhances the learning of cue-reward contingency.

    abstract::The basolateral amygdala (BLA) is critical for associating initially neutral cues with appetitive and aversive stimuli and receives dense neuromodulatory acetylcholine (ACh) projections. We measured BLA ACh signaling and activity of neurons expressing CaMKIIα (a marker for glutamatergic principal cells) in mice during...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.57335

    authors: Crouse RB,Kim K,Batchelor HM,Girardi EM,Kamaletdinova R,Chan J,Rajebhosale P,Pittenger ST,Role LW,Talmage DA,Jing M,Li Y,Gao XB,Mineur YS,Picciotto MR

    更新日期:2020-09-18 00:00:00

  • Finding a worm's internal compass.

    abstract::A pair of neurons is required for nematodes to be able to navigate using the Earth's magnetic field. ...

    journal_title:eLife

    pub_type: 评论,杂志文章

    doi:10.7554/eLife.09666

    authors: Rankin CH,Lin CH

    更新日期:2015-08-05 00:00:00

  • Embryonic transcription factor expression in mice predicts medial amygdala neuronal identity and sex-specific responses to innate behavioral cues.

    abstract::The medial subnucleus of the amygdala (MeA) plays a central role in processing sensory cues required for innate behaviors. However, whether there is a link between developmental programs and the emergence of inborn behaviors remains unknown. Our previous studies revealed that the telencephalic preoptic area (POA) embr...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.21012

    authors: Lischinsky JE,Sokolowski K,Li P,Esumi S,Kamal Y,Goodrich M,Oboti L,Hammond TR,Krishnamoorthy M,Feldman D,Huntsman M,Liu J,Corbin JG

    更新日期:2017-03-13 00:00:00

  • Structural basis of nucleic-acid recognition and double-strand unwinding by the essential neuronal protein Pur-alpha.

    abstract::The neuronal DNA-/RNA-binding protein Pur-alpha is a transcription regulator and core factor for mRNA localization. Pur-alpha-deficient mice die after birth with pleiotropic neuronal defects. Here, we report the crystal structure of the DNA-/RNA-binding domain of Pur-alpha in complex with ssDNA. It reveals base-specif...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.11297

    authors: Weber J,Bao H,Hartlmüller C,Wang Z,Windhager A,Janowski R,Madl T,Jin P,Niessing D

    更新日期:2016-01-08 00:00:00

  • Maternal cortisol is associated with neonatal amygdala microstructure and connectivity in a sexually dimorphic manner.

    abstract::The mechanisms linking maternal stress in pregnancy with infant neurodevelopment in a sexually dimorphic manner are poorly understood. We tested the hypothesis that maternal hypothalamic-pituitary-adrenal axis activity, measured by hair cortisol concentration (HCC), is associated with microstructure, structural connec...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.60729

    authors: Stoye DQ,Blesa M,Sullivan G,Galdi P,Lamb GJ,Black GS,Quigley AJ,Thrippleton MJ,Bastin ME,Reynolds RM,Boardman JP

    更新日期:2020-11-24 00:00:00

  • Phenotypic diversity and temporal variability in a bacterial signaling network revealed by single-cell FRET.

    abstract::We present in vivo single-cell FRET measurements in the Escherichia coli chemotaxis system that reveal pervasive signaling variability, both across cells in isogenic populations and within individual cells over time. We quantify cell-to-cell variability of adaptation, ligand response, as well as steady-state output le...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.27455

    authors: Keegstra JM,Kamino K,Anquez F,Lazova MD,Emonet T,Shimizu TS

    更新日期:2017-12-12 00:00:00