Identifying polyglutamine protein species in situ that best predict neurodegeneration.

Abstract:

:Polyglutamine (polyQ) stretches exceeding a threshold length confer a toxic function to proteins that contain them and cause at least nine neurological disorders. The basis for this toxicity threshold is unclear. Although polyQ expansions render proteins prone to aggregate into inclusion bodies, this may be a neuronal coping response to more toxic forms of polyQ. The exact structure of these more toxic forms is unknown. Here we show that the monoclonal antibody 3B5H10 recognizes a species of polyQ protein in situ that strongly predicts neuronal death. The epitope selectively appears among some of the many low-molecular-weight conformational states assumed by expanded polyQ and disappears in higher-molecular-weight aggregated forms, such as inclusion bodies. These results suggest that protein monomers and possibly small oligomers containing expanded polyQ stretches can adopt a conformation that is recognized by 3B5H10 and is toxic or closely related to a toxic species.

journal_name

Nat Chem Biol

journal_title

Nature chemical biology

authors

Miller J,Arrasate M,Brooks E,Libeu CP,Legleiter J,Hatters D,Curtis J,Cheung K,Krishnan P,Mitra S,Widjaja K,Shaby BA,Lotz GP,Newhouse Y,Mitchell EJ,Osmand A,Gray M,Thulasiramin V,Saudou F,Segal M,Yang XW,Masliah

doi

10.1038/nchembio.694

subject

Has Abstract

pub_date

2011-10-30 00:00:00

pages

925-34

issue

12

eissn

1552-4450

issn

1552-4469

pii

nchembio.694

journal_volume

7

pub_type

杂志文章
  • Ubiquinone accumulation improves osmotic-stress tolerance in Escherichia coli.

    abstract::Bacteria are thought to cope with fluctuating environmental solute concentrations primarily by adjusting the osmolality of their cytoplasm. To obtain insights into the underlying metabolic adaptations, we analyzed the global metabolic response of Escherichia coli to sustained hyperosmotic stress using nontargeted mass...

    journal_title:Nature chemical biology

    pub_type: 杂志文章

    doi:10.1038/nchembio.1437

    authors: Sévin DC,Sauer U

    更新日期:2014-04-01 00:00:00

  • Calcium Green FlAsH as a genetically targeted small-molecule calcium indicator.

    abstract::Intracellular Ca(2+) regulates numerous proteins and cellular functions and can vary substantially over submicron and submillisecond scales, so precisely localized fast detection is desirable. We have created a approximately 1-kDa biarsenical Ca(2+) indicator, called Calcium Green FlAsH (CaGF, 1), to probe [Ca(2+)] su...

    journal_title:Nature chemical biology

    pub_type: 杂志文章

    doi:10.1038/nchembio.2007.4

    authors: Tour O,Adams SR,Kerr RA,Meijer RM,Sejnowski TJ,Tsien RW,Tsien RY

    更新日期:2007-07-01 00:00:00

  • N-terminal domains mediate [2Fe-2S] cluster transfer from glutaredoxin-3 to anamorsin.

    abstract::In eukaryotes, cytosolic monothiol glutaredoxins are proteins implicated in intracellular iron trafficking and sensing via their bound [2Fe-2S] clusters. We define a new role of human cytosolic monothiol glutaredoxin-3 (GRX3) in transferring its [2Fe-2S] clusters to human anamorsin, a physical and functional protein p...

    journal_title:Nature chemical biology

    pub_type: 杂志文章

    doi:10.1038/nchembio.1892

    authors: Banci L,Ciofi-Baffoni S,Gajda K,Muzzioli R,Peruzzini R,Winkelmann J

    更新日期:2015-10-01 00:00:00

  • Eukaryotic DNA polymerases require an iron-sulfur cluster for the formation of active complexes.

    abstract::The eukaryotic replicative DNA polymerases (Pol α, δ and ɛ) and the major DNA mutagenesis enzyme Pol ζ contain two conserved cysteine-rich metal-binding motifs (CysA and CysB) in the C-terminal domain (CTD) of their catalytic subunits. Here we demonstrate by in vivo and in vitro approaches the presence of an essential...

    journal_title:Nature chemical biology

    pub_type: 杂志文章

    doi:10.1038/nchembio.721

    authors: Netz DJ,Stith CM,Stümpfig M,Köpf G,Vogel D,Genau HM,Stodola JL,Lill R,Burgers PM,Pierik AJ

    更新日期:2011-11-27 00:00:00

  • Open access chemical and clinical probes to support drug discovery.

    abstract::Drug discovery resources in academia and industry are not used efficiently, to the detriment of industry and society. Duplication could be reduced, and productivity could be increased, by performing basic biology and clinical proofs of concept within open access industry-academia partnerships. Chemical biologists coul...

    journal_title:Nature chemical biology

    pub_type: 杂志文章

    doi:10.1038/nchembio0709-436

    authors: Edwards AM,Bountra C,Kerr DJ,Willson TM

    更新日期:2009-07-01 00:00:00

  • A PCBP1-BolA2 chaperone complex delivers iron for cytosolic [2Fe-2S] cluster assembly.

    abstract::Hundreds of cellular proteins require iron cofactors for activity, and cells express systems for their assembly and distribution. Molecular details of the cytosolic iron pool used for iron cofactors are lacking, but iron chaperones of the poly(rC)-binding protein (PCBP) family play a key role in ferrous ion distributi...

    journal_title:Nature chemical biology

    pub_type: 杂志文章

    doi:10.1038/s41589-019-0330-6

    authors: Patel SJ,Frey AG,Palenchar DJ,Achar S,Bullough KZ,Vashisht A,Wohlschlegel JA,Philpott CC

    更新日期:2019-09-01 00:00:00

  • Modulating the DNA polymerase β reaction equilibrium to dissect the reverse reaction.

    abstract::DNA polymerases catalyze efficient and high-fidelity DNA synthesis. While this reaction favors nucleotide incorporation, polymerases also catalyze a reverse reaction, pyrophosphorolysis, that removes the DNA primer terminus and generates deoxynucleoside triphosphates. Because pyrophosphorolysis can influence polymeras...

    journal_title:Nature chemical biology

    pub_type: 杂志文章

    doi:10.1038/nchembio.2450

    authors: Shock DD,Freudenthal BD,Beard WA,Wilson SH

    更新日期:2017-10-01 00:00:00

  • Programmable and printable Bacillus subtilis biofilms as engineered living materials.

    abstract::Bacterial biofilms can be programmed to produce living materials with self-healing and evolvable functionalities. However, the wider use of artificial biofilms has been hindered by limitations on processability and functional protein secretion capacity. We describe a highly flexible and tunable living functional mater...

    journal_title:Nature chemical biology

    pub_type: 杂志文章

    doi:10.1038/s41589-018-0169-2

    authors: Huang J,Liu S,Zhang C,Wang X,Pu J,Ba F,Xue S,Ye H,Zhao T,Li K,Wang Y,Zhang J,Wang L,Fan C,Lu TK,Zhong C

    更新日期:2019-01-01 00:00:00

  • Analysis of modular bioengineered antimicrobial lanthipeptides at nanoliter scale.

    abstract::The rise of antibiotic resistance demands the acceleration of molecular diversification strategies to inspire new chemical entities for antibiotic medicines. We report here on the large-scale engineering of ribosomally synthesized and post-translationally modified antimicrobial peptides carrying the ring-forming amino...

    journal_title:Nature chemical biology

    pub_type: 杂志文章

    doi:10.1038/s41589-019-0250-5

    authors: Schmitt S,Montalbán-López M,Peterhoff D,Deng J,Wagner R,Held M,Kuipers OP,Panke S

    更新日期:2019-05-01 00:00:00

  • Synthetic oligonucleotides recruit ILF2/3 to RNA transcripts to modulate splicing.

    abstract::We describe a new technology for recruiting specific proteins to RNA through selective recognition of heteroduplexes formed with chemically modified antisense oligonucleotides (ASOs). Typically, ASOs function by hybridizing to their RNA targets and blocking the binding of single-stranded RNA-binding proteins. Unexpect...

    journal_title:Nature chemical biology

    pub_type: 杂志文章

    doi:10.1038/nchembio.939

    authors: Rigo F,Hua Y,Chun SJ,Prakash TP,Krainer AR,Bennett CF

    更新日期:2012-04-15 00:00:00

  • Chemical phylogenetics of histone deacetylases.

    abstract::The broad study of histone deacetylases in chemistry, biology and medicine relies on tool compounds to derive mechanistic insights. A phylogenetic analysis of class I and II histone deacetylases (HDACs) as targets of a comprehensive, structurally diverse panel of inhibitors revealed unexpected isoform selectivity even...

    journal_title:Nature chemical biology

    pub_type: 杂志文章

    doi:10.1038/nchembio.313

    authors: Bradner JE,West N,Grachan ML,Greenberg EF,Haggarty SJ,Warnow T,Mazitschek R

    更新日期:2010-03-01 00:00:00

  • Two-site recognition of Staphylococcus aureus peptidoglycan by lysostaphin SH3b.

    abstract::Lysostaphin is a bacteriolytic enzyme targeting peptidoglycan, the essential component of the bacterial cell envelope. It displays a very potent and specific activity toward staphylococci, including methicillin-resistant Staphylococcus aureus. Lysostaphin causes rapid cell lysis and disrupts biofilms, and is therefore...

    journal_title:Nature chemical biology

    pub_type: 杂志文章

    doi:10.1038/s41589-019-0393-4

    authors: Gonzalez-Delgado LS,Walters-Morgan H,Salamaga B,Robertson AJ,Hounslow AM,Jagielska E,Sabała I,Williamson MP,Lovering AL,Mesnage S

    更新日期:2020-01-01 00:00:00

  • N6-mA condenses chromatin.

    abstract:: ...

    journal_title:Nature chemical biology

    pub_type: 评论,杂志文章

    doi:10.1038/s41589-018-0199-9

    authors: Song Y

    更新日期:2019-01-01 00:00:00

  • The evolving interface between synthetic biology and functional metagenomics.

    abstract::Nature is a diverse and rich source of bioactive pathways or novel building blocks for synthetic biology. In this Perspective, we describe the emerging research field in which metagenomes are functionally interrogated using synthetic biology. This approach substantially expands the set of identified biological activit...

    journal_title:Nature chemical biology

    pub_type: 杂志文章,评审

    doi:10.1038/s41589-018-0100-x

    authors: van der Helm E,Genee HJ,Sommer MOA

    更新日期:2018-08-01 00:00:00

  • Expanding chemical biology of 2-oxoglutarate oxygenases.

    abstract::Beyond established roles in collagen biosynthesis, hypoxic signaling and fatty acid metabolism, recent reports have now revealed roles for human 2-oxoglutarate-dependent oxygenases in histone and nucleic acid demethylation and in signaling protein hydroxylation. The emerging role of these oxygenases in enabling a mult...

    journal_title:Nature chemical biology

    pub_type: 杂志文章

    doi:10.1038/nchembio0308-152

    authors: Loenarz C,Schofield CJ

    更新日期:2008-03-01 00:00:00

  • The inorganic side of chemical biology.

    abstract::Bioinorganic chemistry remains a vibrant discipline at the interface of chemistry and the biological sciences. Metal ions function in numerous metalloenzymes, are incorporated into pharmaceuticals and imaging agents, and inspire the synthesis of catalysts used to achieve many chemical transformations. ...

    journal_title:Nature chemical biology

    pub_type: 杂志文章

    doi:10.1038/nchembio1006-504

    authors: Lippard SJ

    更新日期:2006-10-01 00:00:00

  • Structural basis for halogenation by iron- and 2-oxo-glutarate-dependent enzyme WelO5.

    abstract::A 2.4-Å-resolution X-ray crystal structure of the carrier-protein-independent halogenase WelO5 in complex with its welwitindolinone precursor substrate, 12-epi-fischerindole U, reveals that the C13 chlorination target is proximal to the anticipated site of the oxo group in a presumptive cis-halo-oxo-iron(IV) (haloferr...

    journal_title:Nature chemical biology

    pub_type: 杂志文章

    doi:10.1038/nchembio.2112

    authors: Mitchell AJ,Zhu Q,Maggiolo AO,Ananth NR,Hillwig ML,Liu X,Boal AK

    更新日期:2016-08-01 00:00:00

  • Nitric oxide activates TRP channels by cysteine S-nitrosylation.

    abstract::Transient receptor potential (TRP) proteins form plasma-membrane cation channels that act as sensors for diverse cellular stimuli. Here, we report a novel activation mechanism mediated by cysteine S-nitrosylation in TRP channels. Recombinant TRPC1, TRPC4, TRPC5, TRPV1, TRPV3 and TRPV4 of the TRPC and TRPV families, wh...

    journal_title:Nature chemical biology

    pub_type: 杂志文章

    doi:10.1038/nchembio821

    authors: Yoshida T,Inoue R,Morii T,Takahashi N,Yamamoto S,Hara Y,Tominaga M,Shimizu S,Sato Y,Mori Y

    更新日期:2006-11-01 00:00:00

  • Suppressors of superoxide production from mitochondrial complex III.

    abstract::Mitochondrial electron transport drives ATP synthesis but also generates reactive oxygen species, which are both cellular signals and damaging oxidants. Superoxide production by respiratory complex III is implicated in diverse signaling events and pathologies, but its role remains controversial. Using high-throughput ...

    journal_title:Nature chemical biology

    pub_type: 杂志文章

    doi:10.1038/nchembio.1910

    authors: Orr AL,Vargas L,Turk CN,Baaten JE,Matzen JT,Dardov VJ,Attle SJ,Li J,Quackenbush DC,Goncalves RL,Perevoshchikova IV,Petrassi HM,Meeusen SL,Ainscow EK,Brand MD

    更新日期:2015-11-01 00:00:00

  • NMR spectroscopy brings invisible protein states into focus.

    abstract::Molecular dynamics are essential for protein function. In some cases these dynamics involve the interconversion between ground state, highly populated conformers and less populated higher energy structures ('excited states') that play critical roles in biochemical processes. Here we describe recent advances in NMR spe...

    journal_title:Nature chemical biology

    pub_type: 杂志文章,评审

    doi:10.1038/nchembio.238

    authors: Baldwin AJ,Kay LE

    更新日期:2009-11-01 00:00:00

  • Chemical hijacking of auxin signaling with an engineered auxin-TIR1 pair.

    abstract::The phytohormone auxin indole-3-acetic acid (IAA) regulates nearly all aspects of plant growth and development. Despite substantial progress in our understanding of auxin biology, delineating specific auxin response remains a major challenge. Auxin regulates transcriptional response via its receptors, TIR1 and AFB F-b...

    journal_title:Nature chemical biology

    pub_type: 杂志文章

    doi:10.1038/nchembio.2555

    authors: Uchida N,Takahashi K,Iwasaki R,Yamada R,Yoshimura M,Endo TA,Kimura S,Zhang H,Nomoto M,Tada Y,Kinoshita T,Itami K,Hagihara S,Torii KU

    更新日期:2018-03-01 00:00:00

  • Selective compounds define Hsp90 as a major inhibitor of apoptosis in small-cell lung cancer.

    abstract::The heat shock protein 90 (Hsp90) has a critical role in malignant transformation. Whereas its ability to maintain the functional conformations of mutant and aberrant oncoproteins is established, a transformation-specific regulation of the antiapoptotic phenotype by Hsp90 is poorly understood. By using selective compo...

    journal_title:Nature chemical biology

    pub_type: 杂志文章

    doi:10.1038/nchembio.2007.10

    authors: Rodina A,Vilenchik M,Moulick K,Aguirre J,Kim J,Chiang A,Litz J,Clement CC,Kang Y,She Y,Wu N,Felts S,Wipf P,Massague J,Jiang X,Brodsky JL,Krystal GW,Chiosis G

    更新日期:2007-08-01 00:00:00

  • A stand-alone adenylation domain forms amide bonds in streptothricin biosynthesis.

    abstract::The streptothricin (ST) antibiotics, produced by Streptomyces bacteria, contain L-β-lysine ((3S)-3,6-diaminohexanoic acid) oligopeptides as pendant chains. Here we describe three unusual nonribosomal peptide synthetases (NRPSs) involved in ST biosynthesis: ORF 5 (a stand-alone adenylation (A) domain), ORF 18 (containi...

    journal_title:Nature chemical biology

    pub_type: 杂志文章

    doi:10.1038/nchembio.1040

    authors: Maruyama C,Toyoda J,Kato Y,Izumikawa M,Takagi M,Shin-ya K,Katano H,Utagawa T,Hamano Y

    更新日期:2012-09-01 00:00:00

  • Precise small-molecule recognition of a toxic CUG RNA repeat expansion.

    abstract::Excluding the ribosome and riboswitches, developing small molecules that selectively target RNA is a longstanding problem in chemical biology. A typical cellular RNA is difficult to target because it has little tertiary, but abundant secondary structure. We designed allele-selective compounds that target such an RNA, ...

    journal_title:Nature chemical biology

    pub_type: 杂志文章

    doi:10.1038/nchembio.2251

    authors: Rzuczek SG,Colgan LA,Nakai Y,Cameron MD,Furling D,Yasuda R,Disney MD

    更新日期:2017-02-01 00:00:00

  • Molecular basis for ubiquitin ligase CRL2FEM1C-mediated recognition of C-degron.

    abstract::Proteome integrity depends on the ubiquitin-proteasome system to degrade unwanted or abnormal proteins. In addition to the N-degrons, C-terminal residues of proteins can also serve as degradation signals (C-degrons) that are recognized by specific cullin-RING ubiquitin ligases (CRLs) for proteasomal degradation. FEM1C...

    journal_title:Nature chemical biology

    pub_type: 杂志文章

    doi:10.1038/s41589-020-00703-4

    authors: Yan X,Wang X,Li Y,Zhou M,Li Y,Song L,Mi W,Min J,Dong C

    更新日期:2021-01-04 00:00:00

  • The catalytic cycle of a thiamin diphosphate enzyme examined by cryocrystallography.

    abstract::Enzymes that use the cofactor thiamin diphosphate (ThDP, 1), the biologically active form of vitamin B(1), are involved in numerous metabolic pathways in all organisms. Although a theory of the cofactor's underlying reaction mechanism has been established over the last five decades, the three-dimensional structures of...

    journal_title:Nature chemical biology

    pub_type: 杂志文章

    doi:10.1038/nchembio788

    authors: Wille G,Meyer D,Steinmetz A,Hinze E,Golbik R,Tittmann K

    更新日期:2006-06-01 00:00:00

  • Dynamic membrane topology in an unassembled membrane protein.

    abstract::Helical membrane proteins are typically assumed to attain stable transmembrane topologies immediately upon co-translational membrane insertion. Here we show that unassembled monomers of the small multidrug resistance (SMR) family exist in a dynamic equilibrium where the N-terminal transmembrane helix flips in and out ...

    journal_title:Nature chemical biology

    pub_type: 杂志文章

    doi:10.1038/s41589-019-0356-9

    authors: Seurig M,Ek M,von Heijne G,Fluman N

    更新日期:2019-10-01 00:00:00

  • Selective irreversible inhibition of a protease by targeting a noncatalytic cysteine.

    abstract::Designing selective inhibitors of proteases has proven problematic, in part because pharmacophores that confer potency exploit the conserved catalytic apparatus. We developed a fundamentally different approach by designing irreversible inhibitors that target noncatalytic cysteines that are structurally unique to a tar...

    journal_title:Nature chemical biology

    pub_type: 杂志文章

    doi:10.1038/nchembio.492

    authors: Hagel M,Niu D,St Martin T,Sheets MP,Qiao L,Bernard H,Karp RM,Zhu Z,Labenski MT,Chaturvedi P,Nacht M,Westlin WF,Petter RC,Singh J

    更新日期:2011-01-01 00:00:00

  • Mycobacterium tuberculosis nitrogen assimilation and host colonization require aspartate.

    abstract::Here we identify the amino acid transporter AnsP1 as the unique aspartate importer in the human pathogen Mycobacterium tuberculosis. Metabolomic analysis of a mutant with an inactive AnsP1 revealed that the transporter is essential for M. tuberculosis to assimilate nitrogen from aspartate. Virulence of the AnsP1 mutan...

    journal_title:Nature chemical biology

    pub_type: 杂志文章

    doi:10.1038/nchembio.1355

    authors: Gouzy A,Larrouy-Maumus G,Wu TD,Peixoto A,Levillain F,Lugo-Villarino G,Guerquin-Kern JL,de Carvalho LP,Poquet Y,Neyrolles O

    更新日期:2013-11-01 00:00:00

  • Genome-wide mutant profiling predicts the mechanism of a Lipid II binding antibiotic.

    abstract::Identifying targets of antibacterial compounds remains a challenging step in the development of antibiotics. We have developed a two-pronged functional genomics approach to predict mechanism of action that uses mutant fitness data from antibiotic-treated transposon libraries containing both upregulation and inactivati...

    journal_title:Nature chemical biology

    pub_type: 杂志文章

    doi:10.1038/s41589-018-0041-4

    authors: Santiago M,Lee W,Fayad AA,Coe KA,Rajagopal M,Do T,Hennessen F,Srisuknimit V,Müller R,Meredith TC,Walker S

    更新日期:2018-06-01 00:00:00