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


: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.






Luk KC,Mills IP,Trojanowski JQ,Lee VM




Has Abstract


2008-11-25 00:00:00












  • Isomers of human alpha-synuclein stabilized by disulfide bonds exhibit distinct structural and aggregative properties.

    abstract::The discovery of three mutants in the -synuclein (alphaSyn) gene and the identification of alphaSyn as the major component of Lewy body have opened a new field for understanding the pathogenesis of Parkinson's disease (PD). AlphaSyn is a natively unfolded protein with unknown function and unspecified conformational he...


    pub_type: 杂志文章


    authors: Jiang C,Chang JY

    更新日期:2007-01-16 00:00:00

  • Replication, repair, and translesion polymerase bypass of N⁶-oxopropenyl-2'-deoxyadenosine.

    abstract::The oxidative stress products malondialdehyde and base propenal react with DNA bases forming the adduction products 3-(2'-deoxy-β-D-erythro-pentofuranosyl)pyrimido[1,2-a]purin-10(3H)-one (M1dG) and N(6)-(oxypropenyl)-2'-deoxyadenosine (OPdA). M1dG is mutagenic in vivo and miscodes in vitro, but little work has been do...


    pub_type: 杂志文章


    authors: Maddukuri L,Shuck SC,Eoff RL,Zhao L,Rizzo CJ,Guengerich FP,Marnett LJ

    更新日期:2013-12-03 00:00:00

  • Hydrolysis of phosphatidylcholine by hepatic lipase in discoidal and spheroidal recombinant high-density lipoprotein.

    abstract::Hepatic lipase (HL) hydrolysis of phosphatidylcholine (PC) was studied in recombinant high-density lipoprotein particles (r-HDL). r-HDL were made from cholate mixed micelles that contained PC, apo AI, and, in some cases, unesterified cholesterol. r-HDL were characterized using chemical composition, nondenaturing gradi...


    pub_type: 杂志文章


    authors: Tansey JT,Thuren TY,Jerome WG,Hantgan RR,Grant K,Waite M

    更新日期:1997-10-07 00:00:00

  • Structural polymorphism and dynamism in the DNA segment GATCTTCCCCCCGGAA: NMR investigations of hairpin, dumbbell, nicked duplex, parallel strands, and i-motif.

    abstract::Structure and dynamism in a DNA segment d-GATCTTCCCCCCGGAA have been investigated by nuclear magnetic resonance (NMR) spectroscopy. At neutral pH, the molecule exists largely as a dumbbell, formed by the association of two hairpins with sticky ends. A small percentage of hairpin is also detectable. The stem of the dum...


    pub_type: 杂志文章


    authors: Singh S,Patel PK,Hosur RV

    更新日期:1997-10-28 00:00:00

  • The ionic track in the F1-ATPase from the thermophilic Bacillus PS3.

    abstract::Only beta-beta cross-links form when the alpha(3)(betaE(395)C)(3)gammaK(36)C (MF(1) residue numbers) double mutant subcomplex of TF(1), the F(1)-ATPase from the thermophilic Bacillus PS3, is slowly inactivated with CuCl(2) in the presence or absence of MgATP. The same slow rate of inactivation and extent of beta-beta ...


    pub_type: 杂志文章


    authors: Bandyopadhyay S,Allison WS

    更新日期:2004-03-09 00:00:00

  • Interaction between Cellobiose Dehydrogenase and Lytic Polysaccharide Monooxygenase.

    abstract::Lytic polysaccharide monooxygenases (LPMOs) are ubiquitous oxidoreductases, facilitating the degradation of polymeric carbohydrates in biomass. Cellobiose dehydrogenase (CDH) is a biologically relevant electron donor in this process, with the electrons resulting from cellobiose oxidation being shuttled from the CDH de...


    pub_type: 杂志文章


    authors: Laurent CVFP,Breslmayr E,Tunega D,Ludwig R,Oostenbrink C

    更新日期:2019-03-05 00:00:00

  • Evidence for the two phosphate binding sites of an analogue of the thioacyl intermediate for the Trypanosoma cruzi glyceraldehyde-3-phosphate dehydrogenase-catalyzed reaction, from its crystal structure.

    abstract::Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) catalyzes the reversible oxidative phosphorylation of d-glyceraldehyde 3-phosphate (GAP) into d-glycerate 1,3-bisphosphate (1,3-diPG) in the presence of NAD(+) and inorganic phosphate (P(i)). Within the active site, two anion-binding sites were ascribed to the binding o...


    pub_type: 杂志文章


    authors: Castilho MS,Pavão F,Oliva G,Ladame S,Willson M,Périé J

    更新日期:2003-06-17 00:00:00

  • DNA binding properties and replication activity of the T antigen related D2 phosphoprotein.

    abstract::According to earlier genetic experiments, a region within the N-terminal 50-100 amino acids may be important for the replication function of T antigen, the initiator protein of simian virus 40 (SV40). We have investigated this possibility using the T antigen related D2 protein in several biochemical assay systems. D2 ...


    pub_type: 杂志文章


    authors: Klausing K,Scheffner M,Scheidtmann KH,Stahl H,Knippers R

    更新日期:1989-03-07 00:00:00

  • Identification of the sites phosphorylated by cyclic AMP-dependent protein kinase on the beta 2 subunit of L-type voltage-dependent calcium channels.

    abstract::Voltage-dependent L-type calcium (Ca) channels are heteromultimeric proteins that are regulated through phosphorylation by cAMP-dependent protein kinase (PKA). We demonstrated that the beta 2 subunit was a substrate for PKA in intact cardiac myocytes through back-phosphorylation experiments. In addition, a heterologou...


    pub_type: 杂志文章


    authors: Gerhardstein BL,Puri TS,Chien AJ,Hosey MM

    更新日期:1999-08-10 00:00:00

  • De-N-acetyllactotriaosylceramide as a novel cationic glycosphingolipid of bovine brain white matter: isolation and characterization.

    abstract::A novel cationic lipid was separated from bovine brain white matter by a series of chromatographies on carboxymethyl-Sephadex and silica gel in chloroform and methanol. Its structure was identified unambiguously as de-N-acetyllactotriaosylceramide (deNAcLc(3)Cer) by mass spectrometry and (1)H NMR. The natural occurren...


    pub_type: 杂志文章


    authors: Hikita T,Tadano-Aritomi K,Iida-Tanaka N,Ishizuka I,Hakomori S

    更新日期:2005-07-12 00:00:00

  • Activity screening of carrier domains within nonribosomal peptide synthetases using complex substrate mixtures and large molecule mass spectrometry.

    abstract::For screening a pool of potential substrates that load carrier domains found in nonribosomal peptide synthetases, large molecule mass spectrometry is shown to be a new, unbiased assay. Combining the high resolving power of Fourier transform mass spectrometry with the ability of adenylation domains to select their own ...


    pub_type: 杂志文章


    authors: Dorrestein PC,Blackhall J,Straight PD,Fischbach MA,Garneau-Tsodikova S,Edwards DJ,McLaughlin S,Lin M,Gerwick WH,Kolter R,Walsh CT,Kelleher NL

    更新日期:2006-02-14 00:00:00

  • Crystal structure analysis of a mutant Escherichia coli thioredoxin in which lysine 36 is replaced by glutamic acid.

    abstract::The structure of a mutant Escherichia coli thioredoxin with a glutamic acid substituted for a conserved lysine at position 36 adjacent to the active site has been solved using molecular replacement and refined at 2.0-A resolution to a crystallographic residual of 19.9%. The mutant was crystallized in an orthorhombic s...


    pub_type: 杂志文章


    authors: Nikkola M,Gleason FK,Fuchs JA,Eklund H

    更新日期:1993-05-18 00:00:00

  • Sequence-Dependent Promoter Escape Efficiency Is Strongly Influenced by Bias for the Pretranslocated State during Initial Transcription.

    abstract::Abortive transcription initiation can be rate-limiting for promoter escape and therefore represents a barrier to productive gene expression. The mechanism for abortive initiation is unknown, but the amount of abortive transcript is known to vary with the composition of the initial transcribed sequence (ITS). Here, we ...


    pub_type: 杂志文章


    authors: Skancke J,Bar N,Kuiper M,Hsu LM

    更新日期:2015-07-21 00:00:00

  • Hypertriglyceridemic VLDL decreases plasminogen binding to endothelial cells and surface-localized fibrinolysis.

    abstract::The effect of normo (NTG)- and hypertriglyceridemic (HTG)-VLDL on cultured human umbilical vein endothelial cell (HUVEC) surface-localized fibrinolysis was examined following pre-incubation with NTG-, HTG-VLDL, LDL (1-20 micrograms/mL) or buffer (control). Ligand binding assays, using 125I-labeled tcu-PA, t-PA, or Glu...


    pub_type: 杂志文章


    authors: Li XN,Koons JC,Benza RL,Parks JM,Varma VK,Bradley WA,Gianturco SH,Taylor KB,Grammer JR,Tabengwa EM,Booyse FM

    更新日期:1996-05-14 00:00:00

  • Reconstitution of 5-hydroxytryptamine transport from cholate-disrupted platelet plasma membrane vesicles.

    abstract::The bile acid cholate disrupts platelet plasma membrane vesicles and inactivates 5-hydroxytryptamine transport activity. The transporter appears not to be solubilized by this procedure, but remains associated with a high molecular weight aggregate. Merely removing cholate does not restore the vesicular structure or tr...


    pub_type: 杂志文章


    authors: Rudnick G,Nelson PJ

    更新日期:1978-11-28 00:00:00

  • Either the carboxyl- or the amino-terminal region of the human ecto-ATPase (E-NTPDase 2) confers detergent and temperature sensitivity to the chicken ecto-ATP-diphosphohydrolase (E-NTPDase 8).

    abstract::Human ecto-ATPase (E-NTPDase 2) and chicken ecto-ATP-diphosphohydrolase (E-NTPDase 8) are cell surface nucleotidases with two transmembranous domains, one each at the N- and C-termini. Hydrolysis of substrates occurs in active sites residing in their extracellular domains. Human ecto-ATPase activity is decreased by NP...


    pub_type: 杂志文章


    authors: Mukasa T,Lee Y,Knowles AF

    更新日期:2005-08-23 00:00:00

  • Thiol regulation of the thylakoid electron transport chain--a missing link in the regulation of photosynthesis?

    abstract::Avoidance of over-reduction of the chloroplast ferredoxin pool is of paramount importance for plants in avoiding oxidative stress. The redox state of this pool can be controlled through regulation of the thylakoid electron transport chain. A model is presented for regulation of this chain via a thiol reduction mechani...


    pub_type: 杂志文章


    authors: Johnson GN

    更新日期:2003-03-18 00:00:00

  • Mechanism of irreversible inhibition of O2 evolution in photosystem II by Tris(hydroxymethyl)aminomethane.

    abstract::The dark reaction of tris(hydroxymethyl)aminomethane (Tris) with the O2-evolving center of photosystem II (PSII) in the S1 state causes irreversible inhibition of O2 evolution. Similar inhibition is observed for several other amines: NH3, CH3NH2, (CH3)2NH, ethanolamine, and 2-amino-2-ethyl-1,3-propanediol. In PSII mem...


    pub_type: 杂志文章


    authors: Rickert KW,Sears J,Beck WF,Brudvig GW

    更新日期:1991-08-13 00:00:00

  • Identification of tyrosine residues that are susceptible to lactoperoxidase-catalyzed iodination on the surface of Escherichia coli 50s ribosomal subunits or 70s ribosomes.

    abstract::Further to our studies on the Escherichia coli 30S ribosomal subunit, the detailed surface topography of both 50S subunits and 70S ribosomes has been investigated by using iodination catalyzed by immobilized lactoperoxidase as the surface probe. In the 50S subunit, only proteins L2, L5, L10, and L11 were iodinated to ...


    pub_type: 杂志文章


    authors: Maly P,Wower J,Zobawa M,Brimacombe R

    更新日期:1983-06-21 00:00:00

  • Ca2+-signaling cycle of a membrane-docking C2 domain.

    abstract::The C2 domain is a Ca2+-dependent, membrane-targeting motif originally discovered in protein kinase C and recently identified in numerous eukaryotic signal-transducing proteins, including cytosolic phospholipase A2 (cPLA2) of the vertebrate inflammation pathway. Intracellular Ca2+ signals recruit the C2 domain of cPLA...


    pub_type: 杂志文章


    authors: Nalefski EA,Slazas MM,Falke JJ

    更新日期:1997-10-07 00:00:00

  • Oxygen infrared spectra of oxyhemoglobins and oxymyoglobins. Evidence of two major liganded O2 structures.

    abstract::The dioxygen stretch bands in infrared spectra for solutions of oxy species of human hemoglobin A and its separated subunits, human mutant hemoglobin Zurich (beta 63His to Arg), rabbit hemoglobin, lamprey hemoglobin, sperm whale myoglobin, bovine myoglobin, and a sea worm chlorocruorin are examined. Each protein exhib...


    pub_type: 杂志文章


    authors: Potter WT,Tucker MP,Houtchens RA,Caughey WS

    更新日期:1987-07-28 00:00:00

  • Acyclic guanosine analogs inhibit DNA polymerases alpha, delta, and epsilon with very different potencies and have unique mechanisms of action.

    abstract::Acyclovir triphosphate, ganciclovir triphosphate and penciclovir triphosphate inhibited DNA polymerases alpha, delta, and epsilon. Each triphosphate preferentially inhibited pol delta, although ganciclovir triphosphate was the most impressive of the three; the Ki for inhibition of pol delta was 2 microM (competitive w...


    pub_type: 杂志文章


    authors: Ilsley DD,Lee SH,Miller WH,Kuchta RD

    更新日期:1995-02-28 00:00:00

  • Characteristics of the isolated apical plasmalemma and intracellular tubulovesicles of the gastric acid secreting cells: demonstration of secretagogue-induced membrane mobilization.

    abstract::Separation of the gradient-purified gastric microsome into two membrane subfractions of distinct enzymatic and phospholipid composition has been achieved by mild SDS (0.033% w/v) treatment followed by sucrose gradient centrifugation of the pig and rabbit gastric microsomes. While the high-density membranes had all of ...


    pub_type: 杂志文章


    authors: Ray TK,Das PK,Nandi J,Banerjee A,Bandopadhyay S

    更新日期:1988-12-13 00:00:00

  • Synergistic Biomineralization Phenomena Created by a Combinatorial Nacre Protein Model System.

    abstract::In the nacre or aragonite layer of the mollusk shell, proteomes that regulate both the early stages of nucleation and nano-to-mesoscale assembly of nacre tablets from mineral nanoparticle precursors exist. Several approaches have been developed to understand protein-associated mechanisms of nacre formation, yet we sti...


    pub_type: 杂志文章


    authors: Chang EP,Roncal-Herrero T,Morgan T,Dunn KE,Rao A,Kunitake JA,Lui S,Bilton M,Estroff LA,Kröger R,Johnson S,Cölfen H,Evans JS

    更新日期:2016-04-26 00:00:00

  • Solid-phase synthesis and side reactions of oligonucleotides containing O-alkylthymine residues.

    abstract::As part of our studies on the molecular mechanism of mutation [Chambers, R. W. (1982) in Molecular and Cellular Mechanisms of Mutagenesis (Lemontt, J. F., & Generoso, W. M., Eds.) pp 121-145, Plenum, New York and London], we wanted to prepare specific oligonucleotides carrying O2- or O4-alkylthymidine residues. Since ...


    pub_type: 杂志文章


    authors: Borowy-Borowski H,Chambers RW

    更新日期:1989-02-21 00:00:00

  • Effect of salt and pH on the reductive half-reaction of Mycobacterium tuberculosis FprA with NADPH.

    abstract::Despite a number of studies, the formation of the Michaelis complexes between ferredoxin-NADP (+) reductases and NADP(H) eluded detailed investigations by rapid kinetic techniques because of their high formation rates. Moreover, the reversible nature of the reaction of hydride ion transfer between these enzymes and NA...


    pub_type: 杂志文章


    authors: Pennati A,Zanetti G,Aliverti A,Gadda G

    更新日期:2008-03-18 00:00:00

  • Cardiac troponin T forms a tetramer in vitro.

    abstract::Cardiac troponin T (cTnT) is a myofibrillar protein essential for calcium-dependent contraction. This property has led to functional studies of developmentally expressed cTnT isoforms and mutants identified in patients with hypertrophic cardiomyopathy. The release of cTnT into the serum following myocardial infarction...


    pub_type: 杂志文章


    authors: Lounes KC,Demeler B,Anderson DE,Gomes AW,Potter JD,Nassar R,Anderson PA

    更新日期:2008-02-19 00:00:00

  • Mutagenic events in Escherichia coli and mammalian cells generated in response to acetylaminofluorene-derived DNA adducts positioned in the Nar I restriction enzyme site.

    abstract::Comparative mutagenesis studies of N-(2'-deoxyguanosin-8-yl)-2-acetylaminofluorene (dG-AAF) and N-(2'-deoxyguanosin-8-yl)-2-aminofluorene (dG-AF) adducts positioned in the Nar I restriction enzyme site were performed using Escherichia coli (E. coli) and simian kidney (COS-7) cells. Oligodeoxynucleotides ((5)(')TCCTCG(...


    pub_type: 杂志文章


    authors: Tan X,Suzuki N,Grollman AP,Shibutani S

    更新日期:2002-12-03 00:00:00

  • Binding and recognition of GATATC target sequences by the EcoRV restriction endonuclease: a study using fluorescent oligonucleotides and fluorescence polarization.

    abstract::Oligonucleotides labeled with hexachlorofluorescein (hex) have enabled the interaction of the restriction endonuclease EcoRV with DNA to be evaluated using fluorescence anisotropy. The sensitivity of hex allowed measurements at oligonucleotide concentrations as low as 1 nM, enabling K(D) values in the low nanomolar ra...


    pub_type: 杂志文章


    authors: Reid SL,Parry D,Liu HH,Connolly BA

    更新日期:2001-02-27 00:00:00

  • Assembly of microtubules from tubulin bearing the nonhydrolyzable guanosine triphosphate analogue GMPPCP [guanylyl 5'-(beta, gamma-methylenediphosphonate)]: variability of growth rates and the hydrolysis of GTP.

    abstract::The growth and shortening of microtubules in guanosine triphosphate-(GTP-) mediated dynamic instability has previously been observed to occur at rates which are remarkably variable (Gildersleeve et al., 1992, Chrétien et al., 1995). Neighboring microtubules observed simultaneously can grow or shorten at different rate...


    pub_type: 杂志文章


    authors: Dye RB,Williams RC Jr

    更新日期:1996-11-12 00:00:00