Mutational analysis of the structural organization of polyglutamine aggregates.

Abstract:

:The formation of amyloid-like aggregates by expanded polyglutamine (polyGln) sequences is suspected to play a critical role in the neuropathology of Huntington's disease and other expanded CAG-repeat diseases. To probe the folding of the polyGln sequence in the aggregate, we replaced Gln-Gln pairs at different sequence intervals with Pro-Gly pairs, elements that are compatible with beta-turn formation and incompatible with beta-extended chain. We find that PGQ9 and PGQ10, peptides consisting of four Q9 or Q10 elements interspersed with PG elements, undergo spontaneous aggregation as efficiently as a Q45 sequence, whereas the corresponding PGQ7 and PGQ8 peptides aggregate much less readily. Furthermore, a PDGQ9 sequence containing d-prolines aggregates more efficiently than the peptide with l-prolines, consistent with beta-turn formation in aggregate structure. Introduction of one additional Pro residue in the center of a Q9 element within PGQ9 completely blocks the peptide's ability to aggregate. This strongly suggests that the Q9 elements are required to be in extended chain for efficient aggregation to occur. We determined the critical nucleus for aggregation nucleation of the PGQ9 peptide to be one, a result identical to that for unbroken polyGln sequences. The PGQN peptide aggregates are structurally quite similar to Q45 aggregates, as judged by heterologous seeding aggregation kinetics, recognition by an anti-polyGln aggregate antibody, and electron microscopy. The results suggest that polyGln aggregate structure consists of alternating elements of extended chain and turn. In the future it should be possible to conduct detailed and interpretable mutational studies in the PGQ9 background.

authors

Thakur AK,Wetzel R

doi

10.1073/pnas.252523899

keywords:

subject

Has Abstract

pub_date

2002-12-24 00:00:00

pages

17014-9

issue

26

eissn

0027-8424

issn

1091-6490

pii

252523899

journal_volume

99

pub_type

杂志文章
  • Communication between oocytes and somatic cells regulates volatile pheromone production in Caenorhabditis elegans.

    abstract::Males of the androdioecious species Caenorhabditis elegans are more likely to attempt to mate with and successfully inseminate C. elegans hermaphrodites that do not concurrently harbor sperm. Although a small number of genes have been implicated in this effect, the mechanism by which it arises remains unknown. In the ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1420439111

    authors: Leighton DH,Choe A,Wu SY,Sternberg PW

    更新日期:2014-12-16 00:00:00

  • High-level expression of a heterologous protein in the milk of transgenic swine using the cDNA encoding human protein C.

    abstract::Transgenic pigs were generated that produced human protein C in their milk at up to 1 g/liter. The gene construct was a fusion gene consisting of the cDNA for human protein C inserted into the first exon of the mouse whey acidic protein gene. These results demonstrate that the mouse whey acidic protein gene contains r...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.89.24.12003

    authors: Velander WH,Johnson JL,Page RL,Russell CG,Subramanian A,Wilkins TD,Gwazdauskas FC,Pittius C,Drohan WN

    更新日期:1992-12-15 00:00:00

  • Evidence for fractional crystallization of wadsleyite and ringwoodite from olivine melts in chondrules entrained in shock-melt veins.

    abstract::Peace River is one of the few shocked members of the L-chondrites clan that contains both high-pressure polymorphs of olivine, ringwoodite and wadsleyite, in diverse textures and settings in fragments entrained in shock-melt veins. Among these settings are complete olivine porphyritic chondrules. We encountered few sq...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0801518105

    authors: Miyahara M,El Goresy A,Ohtani E,Nagase T,Nishijima M,Vashaei Z,Ferroir T,Gillet P,Dubrovinsky L,Simionovici A

    更新日期:2008-06-24 00:00:00

  • Flexible and conductive MXene films and nanocomposites with high capacitance.

    abstract::MXenes, a new family of 2D materials, combine hydrophilic surfaces with metallic conductivity. Delamination of MXene produces single-layer nanosheets with thickness of about a nanometer and lateral size of the order of micrometers. The high aspect ratio of delaminated MXene renders it promising nanofiller in multifunc...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1414215111

    authors: Ling Z,Ren CE,Zhao MQ,Yang J,Giammarco JM,Qiu J,Barsoum MW,Gogotsi Y

    更新日期:2014-11-25 00:00:00

  • Isothermal reactions for the amplification of oligonucleotides.

    abstract::We have devised a class of isothermal reactions for amplifying DNA. These homogeneous reactions rapidly synthesize short oligonucleotides (8-16 bases) specified by the sequence of an amplification template. Versions of the reactions can proceed in either a linear or an exponential amplification mode. Both of these rea...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0730811100

    authors: Van Ness J,Van Ness LK,Galas DJ

    更新日期:2003-04-15 00:00:00

  • Remodeling of synaptic architecture during hippocampal "kindling".

    abstract::The "kindling" phenomenon is associated with long-lasting facilitation of synaptic transmission. A possible mechanism of such facilitation could involve changes in the number of synaptic contacts. However, previous attempts to demonstrate a synaptic morphological alteration that could account for the long-term effects...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.85.9.3260

    authors: Geinisman Y,Morrell F,deToledo-Morrell L

    更新日期:1988-05-01 00:00:00

  • Expression of DNA polymerase {beta} cancer-associated variants in mouse cells results in cellular transformation.

    abstract::Thirty percent of the 189 tumors studied to date express DNA polymerase beta variants. One of these variants was identified in a prostate carcinoma and is altered from isoleucine to methionine at position 260, within the hydrophobic hinge region of the protein. Another variant was identified in a colon carcinoma and i...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0505166102

    authors: Sweasy JB,Lang T,Starcevic D,Sun KW,Lai CC,Dimaio D,Dalal S

    更新日期:2005-10-04 00:00:00

  • Latitudinal difference in biodiversity caused by higher tropical rate of increase.

    abstract::Tropical diversity has generally exceeded temperate diversity in the present and at points in the past, but whether measured differences have remained relatively constant through time has been unknown. Here we examine tropical vs. temperate diversities from the Neogene to Recent using the within-habitat diversity meas...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.122241499

    authors: Buzas MA,Collins LS,Culver SJ

    更新日期:2002-06-11 00:00:00

  • Aberrant expression of receptors for platelet-derived growth factor in an anaplastic thyroid carcinoma cell line.

    abstract::Receptors for platelet-derived growth factor (PDGF) have previously only been found on cells of mesenchymal and glial origin. This study shows PDGF receptors on an anaplastic thyroid carcinoma cell line, C 643, that was found to express thyroglobulin mRNA, confirming its origin from thyroid epithelium. Northern blot a...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.85.23.9302

    authors: Heldin NE,Gustavsson B,Claesson-Welsh L,Hammacher A,Mark J,Heldin CH,Westermark B

    更新日期:1988-12-01 00:00:00

  • Elimination of damaged proteins during differentiation of embryonic stem cells.

    abstract::During mammalian aging, cellular proteins become increasingly damaged: for example, by carbonylation and formation of advanced glycation end products (AGEs). The means to ensure that offspring are born without such damage are unknown. Unexpectedly, we found that undifferentiated mouse ES cells contain high levels of b...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0510944103

    authors: Hernebring M,Brolén G,Aguilaniu H,Semb H,Nyström T

    更新日期:2006-05-16 00:00:00

  • Single-cell RNA sequencing of Trypanosoma brucei from tsetse salivary glands unveils metacyclogenesis and identifies potential transmission blocking antigens.

    abstract::Tsetse-transmitted African trypanosomes must develop into mammalian-infectious metacyclic cells in the fly's salivary glands (SGs) before transmission to a new host. The molecular mechanisms that underlie this developmental process, known as metacyclogenesis, are poorly understood. Blocking the few metacyclic parasite...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1914423117

    authors: Vigneron A,O'Neill MB,Weiss BL,Savage AF,Campbell OC,Kamhawi S,Valenzuela JG,Aksoy S

    更新日期:2020-02-04 00:00:00

  • Why we need to look beyond the glass transition temperature to characterize the dynamics of thin supported polymer films.

    abstract::There is significant variation in the reported magnitude and even the sign of [Formula: see text] shifts in thin polymer films with nominally the same chemistry, film thickness, and supporting substrate. The implicit assumption is that methods used to estimate [Formula: see text] in bulk materials are relevant for inf...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1722024115

    authors: Zhang W,Douglas JF,Starr FW

    更新日期:2018-05-29 00:00:00

  • Effect of centrally administered C75, a fatty acid synthase inhibitor, on ghrelin secretion and its downstream effects.

    abstract::The central administration of the fatty acid synthase (FAS) inhibitor, C75, rapidly suppresses the expression of orexigenic neuropeptides [neuropeptide Y (NPY) and agouti-related protein (AgRP)] and activates expression of anorexigenic neuropeptides [proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated tr...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0500619102

    authors: Hu Z,Cha SH,van Haasteren G,Wang J,Lane MD

    更新日期:2005-03-15 00:00:00

  • A novel repeated element with Z-DNA-forming potential is widely found in evolutionarily diverse eukaryotic genomes.

    abstract::By Southern blotting and hybridization analysis using 32P-labeled poly(dT-dG) . poly(dC-dA) as a probe, we have found, in eukaryotic genomes, a huge number of stretches of dT-dG alternating sequence, a sequence that has been shown to adopt the Z-DNA conformation under some conditions. This sequence was found in all eu...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.79.21.6465

    authors: Hamada H,Petrino MG,Kakunaga T

    更新日期:1982-11-01 00:00:00

  • In vivo and in vitro observations on laminin production by Schwann cells.

    abstract::Recent reports on the dystrophic mouse mutant suggest that the prominent extracellular matrix component of peripheral nerve tissues plays an important role in peripheral nerve development. We have examined the disposition of two prominent extracellular matrix components, fibronectin and laminin, both in mature periphe...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.80.12.3850

    authors: Cornbrooks CJ,Carey DJ,McDonald JA,Timpl R,Bunge RP

    更新日期:1983-06-01 00:00:00

  • Initial hepatic removal of chylomicron remnants is unaffected but endocytosis is delayed in mice lacking the low density lipoprotein receptor.

    abstract::Two endocytic receptors, the low density lipoprotein (LDL) receptor (LDLR) and the LDLR-related protein (LRP), are thought to act in concert in the hepatic uptake of partially metabolized dietary lipoproteins, the chylomicron remnants. We have evaluated the role of these two receptors in the hepatic metabolism of chyl...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.92.10.4611

    authors: Herz J,Qiu SQ,Oesterle A,DeSilva HV,Shafi S,Havel RJ

    更新日期:1995-05-09 00:00:00

  • Structural mechanism of sensing long dsRNA via a noncatalytic domain in human oligoadenylate synthetase 3.

    abstract::The mammalian innate immune system uses several sensors of double-stranded RNA (dsRNA) to develop the interferon response. Among these sensors are dsRNA-activated oligoadenylate synthetases (OAS), which produce signaling 2',5'-linked RNA molecules (2-5A) that activate regulated RNA decay in mammalian tissues. Differen...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1419409112

    authors: Donovan J,Whitney G,Rath S,Korennykh A

    更新日期:2015-03-31 00:00:00

  • Selective cleavage of kinetoplast DNA minicircles promoted by antitrypanosomal drugs.

    abstract::Pentamidine, diminazene aceturate (Berenil), isometamidium chloride (Samorin), and ethidium bromide, which are important antitrypanosomal drugs, promote linearization of Trypanosoma equiperdum minicircle DNA (the principal component of kinetoplast DNA, the mitochondrial DNA in these parasites). This effect occurs at t...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.87.3.950

    authors: Shapiro TA,Englund PT

    更新日期:1990-02-01 00:00:00

  • Plasmid-encoded MucB protein is a DNA polymerase (pol RI) specialized for lesion bypass in the presence of MucA', RecA, and SSB.

    abstract::Replication through damaged sites in DNA requires in Escherichia coli the SOS stress-inducible DNA polymerase V (UmuC), which is specialized for lesion bypass. Homologs of the umuC gene were found on native conjugative plasmids, which often carry multiple antibiotic-resistant genes. MucB is a UmuC homolog present on p...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.200361997

    authors: Goldsmith M,Sarov-Blat L,Livneh Z

    更新日期:2000-10-10 00:00:00

  • Abrupt change of the superconducting gap structure at the nematic critical point in FeSe1-xSx.

    abstract::The emergence of the nematic electronic state that breaks rotational symmetry is one of the most fascinating properties of the iron-based superconductors, and has relevance to cuprates as well. FeSe has a unique ground state in which superconductivity coexists with a nematic order without long-range magnetic ordering,...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1717331115

    authors: Sato Y,Kasahara S,Taniguchi T,Xing X,Kasahara Y,Tokiwa Y,Yamakawa Y,Kontani H,Shibauchi T,Matsuda Y

    更新日期:2018-02-06 00:00:00

  • Genetic confirmation for a central role for TNFα in the direct action of thyroid stimulating hormone on the skeleton.

    abstract::Clinical data showing correlations between low thyroid-stimulating hormone (TSH) levels and high bone turnover markers, low bone mineral density, and an increased risk of osteoporosis-related fractures are buttressed by mouse genetic and pharmacological studies identifying a direct action of TSH on the skeleton. Here ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1308336110

    authors: Sun L,Zhu LL,Lu P,Yuen T,Li J,Ma R,Baliram R,Moonga SS,Liu P,Zallone A,New MI,Davies TF,Zaidi M

    更新日期:2013-06-11 00:00:00

  • Modification of rhodamine staining allows identification of hematopoietic stem cells with preferential short-term or long-term bone marrow-repopulating ability.

    abstract::We have developed a modified rhodamine (Rho) staining procedure to study uptake and efflux in murine hematopoietic stem cells. Distinct populations of Rho++ (bright), Rho+ (dull), and Rho- (negative) cells could be discriminated. Sorted Rho- cells were subjected to a second Rho staining procedure with the P-glycoprote...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.92.19.8901

    authors: Zijlmans JM,Visser JW,Kleiverda K,Kluin PM,Willemze R,Fibbe WE

    更新日期:1995-09-12 00:00:00

  • Nucleotide sequence analysis of feline immunodeficiency virus: genome organization and relationship to other lentiviruses.

    abstract::We determined the complete nucleotide sequence of an infectious proviral molecular clone (FIV-14) of the feline immunodeficiency virus (FIV). FIV-14 has a genome organization similar in complexity to other lentiviruses. In addition to three large open reading frames representing the gag, pol, and env genes, at least f...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.86.20.8088

    authors: Olmsted RA,Hirsch VM,Purcell RH,Johnson PR

    更新日期:1989-10-01 00:00:00

  • Spatial and seasonal patterns in climate change, temperatures, and precipitation across the United States.

    abstract::Changes in climate during the 20th century differ from region to region across the United States. We provide strong evidence that spatial variations in US temperature trends are linked to the hydrologic cycle, and we also present unique information on the seasonal and latitudinal structure of the linkage. We show that...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0808533106

    authors: Portmann RW,Solomon S,Hegerl GC

    更新日期:2009-05-05 00:00:00

  • Possible incipient sympatric ecological speciation in blind mole rats (Spalax).

    abstract::Sympatric speciation has been controversial since it was first proposed as a mode of speciation. Subterranean blind mole rats (Spalacidae) are considered to speciate allopatrically or peripatrically. Here, we report a possible incipient sympatric adaptive ecological speciation in Spalax galili (2n = 52). The study mic...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1222588110

    authors: Hadid Y,Tzur S,Pavlícek T,Šumbera R,Šklíba J,Lövy M,Fragman-Sapir O,Beiles A,Arieli R,Raz S,Nevo E

    更新日期:2013-02-12 00:00:00

  • Functional coupling of Ca2+ channels and ryanodine receptors in cardiac myocytes.

    abstract::In skeletal muscle, dihydropyridine receptors are functionally coupled to ryanodine receptors of the sarcoplasmic reticulum in triadic or diadic junctional complexes. In cardiac muscle direct physical or functional couplings have not been demonstrated. We have tested the hypothesis of functional coupling of L-type Ca2...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.92.1.121

    authors: Sham JS,Cleemann L,Morad M

    更新日期:1995-01-03 00:00:00

  • Establishment and characterization of human T hybrid cells secreting immunoregulatory molecules.

    abstract::Hybridization of human T cells with an azaguanine-resistant human T cell line gave rise to T hybrid cell lines secreting several immunoregulatory molecules. Analyses of karyotypes, HLA phenotypes, and other surface phenotypes, such as T-cell-specific antigens or receptors for sheep erythrocytes and the patterns of mit...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.78.12.7717

    authors: Okada M,Yoshimura N,Kaieda T,Yamamura Y,Kishimoto T

    更新日期:1981-12-01 00:00:00

  • Spider venoms inhibit L-glutamate binding to brain synaptic membrane receptors.

    abstract::The venoms from three spider species, Araneus gemma, Neoscona arabesca, and Argiope aurantia, were shown to inhibit the high-affinity, sodium-independent L-glutamate-binding sites in rat brain synaptic membranes. The same three venoms caused concentration-dependent inhibition of the activity of the glutamate-binding g...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.81.17.5571

    authors: Michaelis EK,Galton N,Early SL

    更新日期:1984-09-01 00:00:00

  • Quality control of ribosomal RNA mediated by polynucleotide phosphorylase and RNase R.

    abstract::Despite their overall accuracy, errors in macromolecular processes, such as rRNA synthesis and ribosome assembly, inevitably occur. However, whether these errors are remediated and how this might be accomplished is not known. In previous work, we showed that a double mutant strain lacking both polynucleotide phosphory...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1231041100

    authors: Cheng ZF,Deutscher MP

    更新日期:2003-05-27 00:00:00

  • Optically functional isoxanthopterin crystals in the mirrored eyes of decapod crustaceans.

    abstract::The eyes of some aquatic animals form images through reflective optics. Shrimp, lobsters, crayfish, and prawns possess reflecting superposition compound eyes, composed of thousands of square-faceted eye units (ommatidia). Mirrors in the upper part of the eye (the distal mirror) reflect light collected from many ommati...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1722531115

    authors: Palmer BA,Hirsch A,Brumfeld V,Aflalo ED,Pinkas I,Sagi A,Rosenne S,Oron D,Leiserowitz L,Kronik L,Weiner S,Addadi L

    更新日期:2018-03-06 00:00:00