Interactions between Hsp70 and the hydrophobic core of alpha-synuclein inhibit fibril assembly.

Abstract:

:Molecular chaperones of the heat shock protein 70 (Hsp70) family counteract protein misfolding in a variety of neurodegenerative disease models. To determine whether human Hsp70 exerts similar effects on the aggregation of alpha-synuclein (alpha-Syn), the key component of insoluble fibrils present in Parkinson's disease, we investigated alpha-Syn fibril assembly in the presence of Hsp70. We found in vitro assembly was efficiently inhibited by substoichiometric concentrations of purified Hsp70 in the absence of cofactors. Experiments using alpha-Syn deletion mutants indicated that interactions between the Hsp70 substrate binding domain and the alpha-Syn core hydrophobic region underlie assembly inhibition. This assembly process was inhibited prior to the elongation stage as we failed to detect any fibrils by electron microscopy. In addition, fluorescence polarization and binding assays suggest that Hsp70 recognizes soluble alpha-Syn species in a highly dynamic and reversible manner. Together, these results provide novel insights into how Hsp70 suppresses alpha-Syn aggregation. Furthermore, our findings suggest that this critical step in Parkinson's disease pathogenesis may be subject to modulation by a common molecular chaperone.

journal_name

Biochemistry

journal_title

Biochemistry

authors

Luk KC,Mills IP,Trojanowski JQ,Lee VM

doi

10.1021/bi801475r

subject

Has Abstract

pub_date

2008-11-25 00:00:00

pages

12614-25

issue

47

eissn

0006-2960

issn

1520-4995

journal_volume

47

pub_type

杂志文章
  • Isolation of seventeen proteins and amino-terminal amino acid sequences of eight proteins from cytoplasmic ribosomes of yeast.

    abstract::Seventeen ribosomal proteins of Saccharomyces cerevisiae were isolated from small ribosomal subunits and disodium ethylenediaminetetraacetate treated 80S ribosomes by chromatography on a column of carboxymethylcellulose and/or by filtration through Sephacryl S-200. The isolated proteins are YS4, YS7, YS8, YS9, YS10, Y...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00262a005

    authors: Otaka E,Higo K,Osawa S

    更新日期:1982-09-14 00:00:00

  • Acetylcholine receptor and ionic channel of Torpedo electroplax: binding of perhydrohistrionicotoxin to membrane and solubilized preparations.

    abstract::The electric organ of the ray, Torpedo ocellata, can serve as a source for both the acetylcholine (ACh) receptor and its ionic channel. The two entities were identified by their specific binding of [3H]ACh and [3H]perhydrohistrionicotoxin ([3H]H12-HTX), respectively. Binding of [3H]H12-HTX was inhibited by certain dru...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00618a023

    authors: Eldefrawi ME,Eldefrawi AT,Mansour NA,Daly JW,Witkop B,Albuquerque EX

    更新日期:1978-12-12 00:00:00

  • Binding properties of chimeric insulin receptors containing the cysteine-rich domain of either the insulin-like growth factor I receptor or the insulin receptor related receptor.

    abstract::We constructed and expressed chimeric receptor cDNAs with insulin receptor exon 3 (residues 191-297 of the cysteine-rich region) replaced with either the comparable region of the insulin-like growth factor I receptor (IGF-IR) or the insulin receptor related receptor (IRR). Both chimeric receptors still could bind insu...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00235a001

    authors: Zhang B,Roth RA

    更新日期:1991-05-28 00:00:00

  • Two crystal structures of the B1 immunoglobulin-binding domain of streptococcal protein G and comparison with NMR.

    abstract::The structure of the 56-residue B1 immunoglobulin-binding domain from streptococcal protein G has been determined in two different crystal forms. The crystal structures were deduced by molecular replacement, based on the structure of the B2 domain (Brookhaven accession code 1PGX). Final R values are 0.174 and 0.198 fo...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:

    authors: Gallagher T,Alexander P,Bryan P,Gilliland GL

    更新日期:1994-04-19 00:00:00

  • Crystal structures of thrombin complexed to a novel series of synthetic inhibitors containing a 5,5-trans-lactone template.

    abstract::The binding modes of four active site-directed, acylating inhibitors of human alpha-thrombin have been determined using X-ray crystallography. These inhibitors (GR157368, GR166081, GR167088, and GR179849) are representatives of a series utilizing a novel 5, 5-trans-lactone template to specifically acylate Ser195 of th...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi9830359

    authors: Jhoti H,Cleasby A,Reid S,Thomas PJ,Weir M,Wonacott A

    更新日期:1999-06-22 00:00:00

  • Constitutive activation of opsin: interaction of mutants with rhodopsin kinase and arrestin.

    abstract::Mutation of Gly90, Glu113, Ala292, and Lys296 in the visual pigment rhodopsin constitutively activates the protein for activation of the G protein transducin. Three of these mutations have been shown to cause two different human diseases. Mutation of Gly90 and Ala292 results in complete night blindness, and mutation o...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00037a035

    authors: Rim J,Oprian DD

    更新日期:1995-09-19 00:00:00

  • Biochemical and functional characterization of recombinant Rhodnius prolixus platelet aggregation inhibitor 1 as a novel lipocalin with high affinity for adenosine diphosphate and other adenine nucleotides.

    abstract::The Rhodnius prolixus aggregation inhibitor 1 (RPAI-1) is a novel blood-sucking salivary molecule that binds to ADP and attenuates platelet aggregation. In this report, we determine the binding constants and specificity of RPAI-1 for adenine nucleotides and its functional significance. By the Hummel-Dreyer method of e...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi011015s

    authors: Francischetti IM,Andersen JF,Ribeiro JM

    更新日期:2002-03-19 00:00:00

  • H3 Cys-110 is in close proximity to the C-terminal regions of H2B and H4 in a nucleosome core with an altered internal arrangement of histones.

    abstract::A particle obtained by nuclease digestion of nucleohistone complexes prepared by direct mixing of histones with DNA in 0.15 M NaCl was indistinguishable by composition and physical properties from nucleosome cores prepared under the same conditions from nucleohistone preannealed in 0.6 M NaCl. We show here that differ...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00476a025

    authors: Kahr WH,Lewis PN,Pulleyblank DE

    更新日期:1990-06-19 00:00:00

  • Kinetic and Bioinformatic Characterization of d-2-Hydroxyglutarate Dehydrogenase from Pseudomonas aeruginosa PAO1.

    abstract::d-2-Hydroxyglutarate dehydrogenase from Pseudomonas aeruginosa PAO1 (PaD2HGDH) catalyzes the oxidation of d-2-hydroxyglutarate to 2-ketoglutarate, which is a necessary step in the serine biosynthetic pathway. The dependence of P. aeruginosa on PaD2HGDH makes the enzyme a potential therapeutic target against P. aerugin...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/acs.biochem.0c00832

    authors: Quaye JA,Gadda G

    更新日期:2020-12-29 00:00:00

  • Using Tetracysteine-Tagged TDP-43 with a Biarsenical Dye To Monitor Real-Time Trafficking in a Cell Model of Amyotrophic Lateral Sclerosis.

    abstract::TAR DNA-binding protein 43 (TDP-43) has been identified as the major constituent of the proteinaceous inclusions that are characteristic of most forms of amyotrophic lateral sclerosis (ALS) and ubiquitin positive frontotemporal lobar degeneration (FTLD). Wild type TDP-43 inclusions are a pathological hallmark of >95% ...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/acs.biochem.9b00592

    authors: Ng JSW,Hanspal MA,Matharu NS,Barros TP,Esbjörner EK,Wilson MR,Yerbury JJ,Dobson CM,Kumita JR

    更新日期:2019-10-01 00:00:00

  • Identification of tyrosine residues on ELMO1 that are phosphorylated by the Src-family kinase Hck.

    abstract::The SH3 and SH2 domains of hematopoietic cell kinase (Hck) play important roles in substrate targeting. To identify new components of Hck signaling pathways, we identified proteins that bind to the SH3 domain of Hck (Scott et al. (2002) J. Biol. Chem. 277, 28238). One such protein was ELMO1, the mammalian orthologue o...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi0500832

    authors: Yokoyama N,deBakker CD,Zappacosta F,Huddleston MJ,Annan RS,Ravichandran KS,Miller WT

    更新日期:2005-06-21 00:00:00

  • Interactions of the DNA Repair Enzyme Human Thymine DNA Glycosylase with Cognate and Noncognate DNA.

    abstract::Glycosylases specifically recognize and flip their target base out of the DNA helix into the enzyme's active site. Our simulations show that a partially flipped state, already present in free DNA carrying a T:G mispair, becomes the more probable state compared to the closed state after binding of thymine DNA glycosyla...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/acs.biochem.8b00409

    authors: Kanaan N,Imhof P

    更新日期:2018-10-02 00:00:00

  • Neurotoxins active on insects: amino acid sequences, chemical modifications, and secondary structure estimation by circular dichroism of toxins from the scorpion Androctonus australis Hector.

    abstract::Two scorpion neurotoxins active only on insects, the insect toxins AaH IT1 and AaH IT2, were purified from the venom of scorpions Androctonus australis Hector collected in Tozeur (Tunisia) and characterized. AaH IT2 was sequenced and found to differ in four amino acid positions from AaH IT, the single previously seque...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00458a021

    authors: Loret EP,Mansuelle P,Rochat H,Granier C

    更新日期:1990-02-13 00:00:00

  • Conformation as the determinant of saccharide binding in concanavalin A: Ca2+-concanavalin A complexes.

    abstract::The existence of two conformational states of concanavalin A (Con A) with different metal ion binding properties has been recently demonstrated (Brown, R. D., Brewer, C. F., & Koenig, S. H. (1977) Biochemistry 16, 3883). Introduction of Mn2+ to the S1 site and Ca2+ to the S2 site of apo-Con A was shown to induce a con...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00613a022

    authors: Koenig SH,Brewer CF,Brown RD 3rd

    更新日期:1978-10-03 00:00:00

  • Site-directed alteration of three active-site residues of a pyruvoyl-dependent histidine decarboxylase.

    abstract::The active site of histidine decarboxylase (HDC) from Lactobacillus 30a contains a pyruvoyl cofactor sitting at the interface of two molecules in a trimer. Although exhibiting hyperbolic kinetics at pH 4.8, near its optimum, HDC is cooperative at pH 7.6, indicating that the units of the trimer communicate. A Hill plot...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00069a032

    authors: Pishko EJ,Robertus JD

    更新日期:1993-05-11 00:00:00

  • A distinctive RNA fold: the solution structure of an analogue of the yeast tRNAPhe T Psi C domain.

    abstract::The structure of an analogue of the yeast tRNAPhe T Psi C stem-loop has been determined by NMR spectroscopy and restrained molecular dynamics. The molecule contained the highly conserved modification ribothymidine at its naturally occurring position. The ribothymidine-modified T Psi C stem-loop is the product of the m...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi990118w

    authors: Koshlap KM,Guenther R,Sochacka E,Malkiewicz A,Agris PF

    更新日期:1999-07-06 00:00:00

  • Structure of ATP-bound human ATP:cobalamin adenosyltransferase.

    abstract::Mutations in the gene encoding human ATP:cobalamin adenosyltransferase (hATR) can result in the metabolic disorder known as methylmalonic aciduria (MMA). This enzyme catalyzes the final step in the conversion of cyanocobalamin (vitamin B12) to the essential human cofactor adenosylcobalamin. Here we present the 2.5 A c...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi061396f

    authors: Schubert HL,Hill CP

    更新日期:2006-12-26 00:00:00

  • Complement protein C1q recognizes enzymatically modified low-density lipoprotein through unesterified fatty acids generated by cholesterol esterase.

    abstract::We previously reported that enzymatically modified low-density lipoprotein (E-LDL) particles obtained by LDL treatment with trypsin and then cholesterol esterase are recognized by C1q and activate the C1 complex of complement. The objective of this study was to identify the E-LDL component(s) recognized by C1q. In add...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi9021022

    authors: Biro A,Ling WL,Arlaud GJ

    更新日期:2010-03-16 00:00:00

  • Calmodulin-dependent protein phosphatase: a developmental study.

    abstract::Calmodulin-dependent protein phosphatase, one of the major calmodulin-binding proteins in bovine brain, dephosphorylates casein with a specific activity of 15 nmol mg-1 min-1 at 30 degrees C. The stimulation of phosphatase activity by calmodulin is reversed by ethylene glycol bis (beta-aminoethyl ether)-N,N,N',N'-tetr...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00284a014

    authors: Tallant EA,Cheung WY

    更新日期:1983-07-19 00:00:00

  • Interaction of a paramagnetic analogue of oxaloacetate with citrate synthase.

    abstract::Electron paramagnetic resonance studies have indicated that nitrosodisulfonate binds to pig heart citrate synthase. Titration of the enzyme with nitrosodisulfonate revealed several binding sites for the probe per subunit with one site (KD approximately 0.1 mM) having a greater affinity than the others. The substrate, ...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00584a028

    authors: Weidman SW,Drysdale GR

    更新日期:1979-08-21 00:00:00

  • Substrate specificity and sequence preference of G:T mismatch repair: incision at G:T, O6-methylguanine:T, and G:U mispairs in DNA by human cell extracts.

    abstract::Extracts of two human glioma cell lines (lacking O6-methylguanine DNA-methyltransferase) (i.e., A1235 and its alkylation-resistant derivative A1235-MR4) were examined for their ability to execute strand incision at different base mismatches in model (45-bp) DNA. These heteroduplex substrates were of the same sequence ...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi020239n

    authors: Lari SU,Al-Khodairy F,Paterson MC

    更新日期:2002-07-23 00:00:00

  • Signal recognition particle (SRP) and SRP receptor: a new paradigm for multistate regulatory GTPases.

    abstract::The GTP-binding proteins or GTPases comprise a superfamily of proteins that provide molecular switches in numerous cellular processes. The "GTPase switch" paradigm, in which a GTPase acts as a bimodal switch that is turned "on" and "off" by external regulatory factors, has been used to interpret the regulatory mechani...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi9006989

    authors: Shan SO,Schmid SL,Zhang X

    更新日期:2009-07-28 00:00:00

  • Intestinal absorption of dietary cholesteryl ester is decreased but retinyl ester absorption is normal in carboxyl ester lipase knockout mice.

    abstract::Carboxyl ester lipase (CEL; EC 3.1.1.13) hydrolyzes cholesteryl esters and retinyl esters in vitro. In vivo, pancreatic CEL is thought to liberate cholesterol and retinol from their esters prior to absorption in the intestine. CEL is also a major lipase in the breast milk of many mammals, including humans and mice, an...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi981679a

    authors: Weng W,Li L,van Bennekum AM,Potter SH,Harrison EH,Blaner WS,Breslow JL,Fisher EA

    更新日期:1999-03-30 00:00:00

  • Isatins Inhibit N5-CAIR Synthetase by a Substrate Depletion Mechanism.

    abstract::The continued rise of antibiotic-resistant infections coupled with the limited pipeline of new antimicrobials highlights the pressing need for the development of new antibacterial agents. One potential pathway for new agents is de novo purine biosynthesis as studies have shown that bacteria and lower eukaryotes synthe...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/acs.biochem.8b00939

    authors: Streeter CC,Lin Q,Firestine SM

    更新日期:2019-04-30 00:00:00

  • DNA sequence-specific recognition by the Saccharomyces cerevisiae "TATA" binding protein: promoter-dependent differences in the thermodynamics and kinetics of binding.

    abstract::The equilibrium binding and association kinetics of the Saccharomyces cerevisiae TATA Binding Protein (TBP) to the E4 and Major Late promoters of adenovirus (TATATATA and TATAAAAG, respectively), have been directly compared by quantitative DNase I titration and quench-flow "footprinting". The equilibrium binding of TB...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi981072u

    authors: Petri V,Hsieh M,Jamison E,Brenowitz M

    更新日期:1998-11-10 00:00:00

  • Emerging Functional Differences between the Synaptotagmin and Ferlin Calcium Sensor Families.

    abstract::The ferlin family proteins have emerged as multi-C2 domain regulators of calcium-triggered membrane fusion and fission events. While initially determined to share many of the features of members of the synaptotagmin family of calcium sensors, ferlins in more recent studies have been found to interact directly with non...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/acs.biochem.7b00928

    authors: Johnson CP

    更新日期:2017-12-12 00:00:00

  • Sugar recognition by CscB and LacY.

    abstract::The sucrose permease (CscB) and lactose permease (LacY) of Escherichia coli belong to the oligosaccharide/H(+) symporter subfamily of the major facilitator superfamily, and both catalyze sugar/H(+) symport across the cytoplasmic membrane. Thus far, there is no common substrate for the two permeases; CscB transports su...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi201592y

    authors: Sugihara J,Smirnova I,Kasho V,Kaback HR

    更新日期:2011-12-27 00:00:00

  • Fate of the (2Fe-2S)(2+) cluster of Escherichia coli biotin synthase during reaction: a Mössbauer characterization.

    abstract::Biotin synthase, the enzyme which catalyzes the last step of the biosynthesis of biotin, contains only (2Fe-2S)(2+) clusters when isolated under aerobic conditions. Previous results showed that reduction by dithionite or photoreduced deazaflavin converts the (2Fe-2S)(2+) to (4Fe-4S)(2+,+). However, until now, no detai...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi034426c

    authors: Tse Sum Bui B,Benda R,Schünemann V,Florentin D,Trautwein AX,Marquet A

    更新日期:2003-07-29 00:00:00

  • Interaction of ammonia with the water splitting enzyme of photosystem II.

    abstract::The effects of NH3 on the oxygen evolving enzyme have been investigated with EPR and steady-state O2 evolution. The following results were obtained. At low light intensity O2 evolution occurs in all centers even though ammonia is bound. This binding occurs in the S2 state and results in a modification of the multiline...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00453a003

    authors: Boussac A,Rutherford AW,Styring S

    更新日期:1990-01-09 00:00:00

  • Studies on the microsomal mixed function oxidase system: redox properties of detergent-solubilized NADPH-cytochrome P-450 reductase.

    abstract::Hepatic microsomal NADPH-cytochrome P-450 reductase was solubilized from rabbit liver microsomes in the presence of detergents and purified to homogeneity by column chromatography. The purified reductase had a molecular weight of 78 000 and contained 1 mol each of FAD and FMN per mol of enzyme. On reduction with NADPH...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00604a032

    authors: Iyanagi T,Anan FK,Imai Y,Mason HS

    更新日期:1978-05-30 00:00:00