Polyglutamine domain flexibility mediates the proximity between flanking sequences in huntingtin.

Abstract:

:Huntington disease (HD) is a neurodegenerative disorder caused by a CAG expansion within the huntingtin gene that encodes a polymorphic glutamine tract at the amino terminus of the huntingtin protein. HD is one of nine polyglutamine expansion diseases. The clinical threshold of polyglutamine expansion for HD is near 37 repeats, but the mechanism of this pathogenic length is poorly understood. Using Förster resonance energy transfer, we describe an intramolecular proximity between the N17 domain and the downstream polyproline region that flanks the polyglutamine tract of huntingtin. Our data support the hypothesis that the polyglutamine tract can act as a flexible domain, allowing the flanking domains to come into close spatial proximity. This flexibility is impaired with expanded polyglutamine tracts, and we can detect changes in huntingtin conformation at the pathogenic threshold for HD. Altering the structure of N17, either via phosphomimicry or with small molecules, also affects the proximity between the flanking domains. The structural capacity of N17 to fold back toward distal regions within huntingtin requires an interacting protein, protein kinase C and casein kinase 2 substrate in neurons 1 (PACSIN1). This protein has the ability to bind both N17 and the polyproline region, stabilizing the interaction between these two domains. We also developed an antibody-based FRET assay that can detect conformational changes within endogenous huntingtin in wild-type versus HD fibroblasts. Therefore, we hypothesize that wild-type length polyglutamine tracts within huntingtin can form a flexible domain that is essential for proper functional intramolecular proximity, conformations, and dynamics.

authors

Caron NS,Desmond CR,Xia J,Truant R

doi

10.1073/pnas.1301342110

subject

Has Abstract

pub_date

2013-09-03 00:00:00

pages

14610-5

issue

36

eissn

0027-8424

issn

1091-6490

pii

1301342110

journal_volume

110

pub_type

杂志文章
  • Hinge region of Arabidopsis phyA plays an important role in regulating phyA function.

    abstract::Phytochrome A (phyA) is the only plant photoreceptor that perceives far-red light and then mediates various responses to this signal. Phosphorylation and dephosphorylation of oat phyA have been extensively studied, and it was shown that phosphorylation of a serine residue in the hinge region of oat phyA could regulate...

    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.1813162115

    authors: Zhou Y,Yang L,Duan J,Cheng J,Shen Y,Wang X,Han R,Li H,Li Z,Wang L,Terzaghi W,Zhu D,Chen H,Deng XW,Li J

    更新日期:2018-12-11 00:00:00

  • Titanospirillum velox: a huge, speedy, sulfur-storing spirillum from Ebro Delta microbial mats.

    abstract::A long (20-30 micrometer), wide (3-5 micrometer) microbial-mat bacterium from the Ebro Delta (Tarragona, Spain) was grown in mixed culture and videographed live. Intracellular elemental sulfur globules and unique cell termini were observed in scanning-electron-microprobe and transmission-electron micrographs. A polar ...

    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.96.20.11584

    authors: Guerrero R,Haselton A,Solé M,Wier A,Margulis L

    更新日期:1999-09-28 00:00:00

  • C2'-endo nucleotides as molecular timers suggested by the folding of an RNA domain.

    abstract::A striking and widespread observation is that higher-order folding for many RNAs is very slow, often requiring minutes. In some cases, slow folding reflects the need to disrupt stable, but incorrect, interactions. However, a molecular explanation for slow folding in most RNAs is unknown. The specificity domain of 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.0901319106

    authors: Mortimer SA,Weeks KM

    更新日期:2009-09-15 00:00:00

  • Prediction of protein folding class using global description of amino acid sequence.

    abstract::We present a method for predicting protein folding class based on global protein chain description and a voting process. Selection of the best descriptors was achieved by a computer-simulated neural network trained on a data base consisting of 83 folding classes. Protein-chain descriptors include overall composition, ...

    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.92.19.8700

    authors: Dubchak I,Muchnik I,Holbrook SR,Kim SH

    更新日期:1995-09-12 00:00:00

  • Intracellular membrane flow: reconstitution of transition vesicle formation and function in a cell-free system.

    abstract::Transfer of membrane between endoplasmic reticulum and Golgi apparatus in situ is considered to occur via 60-nm transition vesicles derived from part-rough, part-smooth transition elements of the endoplasmic reticulum. A procedure is described for the isolation of a fraction enriched in these transition elements from ...

    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.84.17.6098

    authors: Nowack DD,Morré DM,Paulik M,Keenan TW,Morré DJ

    更新日期:1987-09-01 00:00:00

  • Distinct effectors of platelet-derived growth factor receptor-alpha signaling are required for cell survival during embryogenesis.

    abstract::Platelet-derived growth factor receptor (PDGFR) signaling is essential for normal embryonic development in many organisms, including frog, mouse, zebrafish, and sea urchin. The mode of action of PDGFR signaling during early development is poorly understood, however, mostly because inhibition of signaling through eithe...

    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.0502885102

    authors: Van Stry M,Kazlauskas A,Schreiber SL,Symes K

    更新日期:2005-06-07 00:00:00

  • 3.3 Å structure of Niemann-Pick C1 protein reveals insights into the function of the C-terminal luminal domain in cholesterol transport.

    abstract::Niemann-Pick C1 (NPC1) and NPC2 proteins are indispensable for the export of LDL-derived cholesterol from late endosomes. Mutations in these proteins result in Niemann-Pick type C disease, a lysosomal storage disease. Despite recent reports of the NPC1 structure depicting its overall architecture, the function of its ...

    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.1711716114

    authors: Li X,Lu F,Trinh MN,Schmiege P,Seemann J,Wang J,Blobel G

    更新日期:2017-08-22 00:00:00

  • Molecular cloning of beta 3 subunit, a third form of the G protein beta-subunit polypeptide.

    abstract::The signal-transducing guanine nucleotide-binding regulatory (G) proteins are heterotrimers composed of three subunits--alpha, beta, and gamma. Although multiple distinctive forms of the alpha subunit have been described, only two forms of the beta subunits of the G proteins have been identified. To investigate furthe...

    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.87.6.2329

    authors: Levine MA,Smallwood PM,Moen PT Jr,Helman LJ,Ahn TG

    更新日期:1990-03-01 00:00:00

  • Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: prevention of reperfusion injury.

    abstract::The chemokine CXC ligand 8 (CXCL8)/IL-8 and related agonists recruit and activate polymorphonuclear cells by binding the CXC chemokine receptor 1 (CXCR1) and CXCR2. Here we characterize the unique mode of action of a small-molecule inhibitor (Repertaxin) of CXCR1 and CXCR2. Structural and biochemical data are consiste...

    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.0402090101

    authors: Bertini R,Allegretti M,Bizzarri C,Moriconi A,Locati M,Zampella G,Cervellera MN,Di Cioccio V,Cesta MC,Galliera E,Martinez FO,Di Bitondo R,Troiani G,Sabbatini V,D'Anniballe G,Anacardio R,Cutrin JC,Cavalieri B,Mainiero F

    更新日期:2004-08-10 00:00:00

  • Strong metal-metal Pauli repulsion leads to repulsive metallophilicity in closed-shell d8 and d10 organometallic complexes.

    abstract::Metallophilicity is defined as the interaction among closed-shell metal centers, the origin of which remains controversial, particularly for the roles of spd orbital hybridization (mixing of the spd atomic orbitals of the metal atom in the molecular orbitals of metal complex) and the relativistic effect. Our studies 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.2019265118

    authors: Wan Q,Yang J,To WP,Che CM

    更新日期:2021-01-05 00:00:00

  • Development and application of a suite of polysaccharide-degrading enzymes for analyzing plant cell walls.

    abstract::To facilitate analysis of plant cell wall polysaccharide structure and composition, we cloned 74 genes encoding polysaccharide-degrading enzymes from Aspergillus nidulans, Aspergillus fumigatus, and Neurospora crassa and expressed the genes as secreted proteins with C-terminal Myc and 6x His tags. Most of the recombin...

    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.0604632103

    authors: Bauer S,Vasu P,Persson S,Mort AJ,Somerville CR

    更新日期:2006-07-25 00:00:00

  • Structural basis for cooperative regulation of KIX-mediated transcription pathways by the HTLV-1 HBZ activation domain.

    abstract::The human T cell leukemia virus I basic leucine zipper protein (HTLV-1 HBZ) maintains chronic viral infection and promotes leukemogenesis through poorly understood mechanisms involving interactions with the KIX domain of the transcriptional coactivator CBP and its paralog p300. The KIX domain binds regulatory proteins...

    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.1810397115

    authors: Yang K,Stanfield RL,Martinez-Yamout MA,Dyson HJ,Wilson IA,Wright PE

    更新日期:2018-10-02 00:00:00

  • Different personal propensities among scientists relate to deeper vs. broader knowledge contributions.

    abstract::Scientific journal publications, and their contributions to knowledge, can be described by their depth (specialized, domain-specific knowledge extensions) and breadth (topical scope, including spanning multiple knowledge domains). Toward generating hypotheses about how scientists' personal dispositions would uniquely ...

    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.1421286112

    authors: Bateman TS,Hess AM

    更新日期:2015-03-24 00:00:00

  • The role of nanostructure in the wetting behavior of mixed-monolayer-protected metal nanoparticles.

    abstract::Self-assembled monolayer-protected nanoparticles are promising candidates for applications, such as sensing and drug delivery, in which the molecular ligands' interactions with the surrounding environment play a crucial role. We recently showed that, when gold nanoparticles are coated with a binary mixture of immiscib...

    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.0803929105

    authors: Centrone A,Penzo E,Sharma M,Myerson JW,Jackson AM,Marzari N,Stellacci F

    更新日期:2008-07-22 00:00:00

  • Maximum leaf conductance driven by CO2 effects on stomatal size and density over geologic time.

    abstract::Stomatal pores are microscopic structures on the epidermis of leaves formed by 2 specialized guard cells that control the exchange of water vapor and CO(2) between plants and the atmosphere. Stomatal size (S) and density (D) determine maximum leaf diffusive (stomatal) conductance of CO(2) (g(c(max))) to sites of assim...

    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.0904209106

    authors: Franks PJ,Beerling DJ

    更新日期:2009-06-23 00:00:00

  • An essential role for the phosphatidylinositol transfer protein in the scission of coatomer-coated vesicles from the trans-Golgi network.

    abstract::We identified the phosphatidylinositol transfer protein (PITP) as being responsible for a powerful latent, nucleotide-independent, Golgi-vesiculating activity that is present in the cytosol but is only manifested as an uncontrolled activity in a cytosolic protein subfraction, in which it is separated from regulatory c...

    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.95.19.11181

    authors: Simon JP,Morimoto T,Bankaitis VA,Gottlieb TA,Ivanov IE,Adesnik M,Sabatini DD

    更新日期:1998-09-15 00:00:00

  • Accelerated tumor development in interferon-treated B6.C-Hyal-1 a mice.

    abstract::The Hyal-1 locus, which we have previously described and mapped to mouse chromosome 9, influences the serum levels and molecular weight forms of hyaluronidase. We have also shown that the growth of two transplantable tumors, the 3LL carcinoma and the B16F10 melanoma, is influenced by the alleles at Hyal-1, in that 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.90.12.5708

    authors: De Maeyer-Guignard J,Lauret E,Eusèbe L,De Maeyer E

    更新日期:1993-06-15 00:00:00

  • DC-SIGN activation mediates the differential effects of SAP and CRP on the innate immune system and inhibits fibrosis in mice.

    abstract::Fibrosis is caused by scar tissue formation in internal organs and is associated with 45% of deaths in the United States. Two closely related human serum proteins, serum amyloid P (SAP) and C-reactive protein (CRP), strongly affect fibrosis. In multiple animal models, and in Phase 1 and Phase 2 clinical trials, SAP af...

    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.1500956112

    authors: Cox N,Pilling D,Gomer RH

    更新日期:2015-07-07 00:00:00

  • Human POT1 disrupts telomeric G-quadruplexes allowing telomerase extension in vitro.

    abstract::The POT1 (protection of telomeres 1) protein binds the ssDNA overhangs at the ends of chromosomes in diverse eukaryotes. POT1 is essential for chromosome end-protection, as best demonstrated in fission yeast. In human cells, hPOT1 is also involved in telomere-length regulation. We now show that telomeric oligonucleoti...

    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.0504744102

    authors: Zaug AJ,Podell ER,Cech TR

    更新日期:2005-08-02 00:00:00

  • Equatorial convergence of India and early Cenozoic climate trends.

    abstract::India's northward flight and collision with Asia was a major driver of global tectonics in the Cenozoic and, we argue, of atmospheric CO(2) concentration (pCO(2)) and thus global climate. Subduction of Tethyan oceanic crust with a carpet of carbonate-rich pelagic sediments deposited during transit beneath the high-pro...

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

    pub_type: 历史文章,杂志文章

    doi:10.1073/pnas.0805382105

    authors: Kent DV,Muttoni G

    更新日期:2008-10-21 00:00:00

  • The hydrophobic moment detects periodicity in protein hydrophobicity.

    abstract::Periodicities in the polar/apolar character of the amino acid sequence of a protein can be examined by assigning to each residue a numerical hydrophobicity and searching for periodicity in the resulting one-dimensional function. The strength of each periodic component is the quantity that has been termed the hydrophob...

    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.81.1.140

    authors: Eisenberg D,Weiss RM,Terwilliger TC

    更新日期:1984-01-01 00:00:00

  • Draft genome of the peanut A-genome progenitor (Arachis duranensis) provides insights into geocarpy, oil biosynthesis, and allergens.

    abstract::Peanut or groundnut (Arachis hypogaea L.), a legume of South American origin, has high seed oil content (45-56%) and is a staple crop in semiarid tropical and subtropical regions, partially because of drought tolerance conferred by its geocarpic reproductive strategy. We present a draft genome of the peanut A-genome 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.1600899113

    authors: Chen X,Li H,Pandey MK,Yang Q,Wang X,Garg V,Li H,Chi X,Doddamani D,Hong Y,Upadhyaya H,Guo H,Khan AW,Zhu F,Zhang X,Pan L,Pierce GJ,Zhou G,Krishnamohan KA,Chen M,Zhong N,Agarwal G,Li S,Chitikineni A,Zhang GQ

    更新日期:2016-06-14 00:00:00

  • Structural insight on the recognition of surface-bound opsonins by the integrin I domain of complement receptor 3.

    abstract::Complement receptors (CRs), expressed notably on myeloid and lymphoid cells, play an essential function in the elimination of complement-opsonized pathogens and apoptotic/necrotic cells. In addition, these receptors are crucial for the cross-talk between the innate and adaptive branches of the immune system. CR3 (also...

    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.1311261110

    authors: Bajic G,Yatime L,Sim RB,Vorup-Jensen T,Andersen GR

    更新日期:2013-10-08 00:00:00

  • Divergent gene copies in the asexual class Bdelloidea (Rotifera) separated before the bdelloid radiation or within bdelloid families.

    abstract::Rotifers of the asexual class Bdelloidea are unusual in possessing two or more divergent copies of every gene that has been examined. Phylogenetic analysis of the heat-shock gene hsp82 and the TATA-box-binding protein gene tbp in multiple bdelloid species suggested that for each gene, each copy belonged to one of two ...

    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.2136686100

    authors: Mark Welch DB,Cummings MP,Hillis DM,Meselson M

    更新日期:2004-02-10 00:00:00

  • A missense mutation in the human liver/bone/kidney alkaline phosphatase gene causing a lethal form of hypophosphatasia.

    abstract::Hypophosphatasia is an inherited disorder characterized by defective bone mineralization and a deficiency of serum and tissue liver/bone/kidney alkaline phosphatase (L/B/K ALP) activity. Clinical severity is variable, ranging from death in utero (due to severe rickets) to pathologic fractures first presenting in adult...

    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.85.20.7666

    authors: Weiss MJ,Cole DE,Ray K,Whyte MP,Lafferty MA,Mulivor RA,Harris H

    更新日期:1988-10-01 00:00:00

  • Hierarchical mesoporous perovskite La0.5Sr0.5CoO2.91 nanowires with ultrahigh capacity for Li-air batteries.

    abstract::Lithium-air batteries have captured worldwide attention due to their highest energy density among the chemical batteries. To provide continuous oxygen channels, here, we synthesized hierarchical mesoporous perovskite La(0.5)Sr(0.5)CoO(2.91) (LSCO) nanowires. We tested the intrinsic oxygen reduction reaction (ORR) and ...

    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.1210315109

    authors: Zhao Y,Xu L,Mai L,Han C,An Q,Xu X,Liu X,Zhang Q

    更新日期:2012-11-27 00:00:00

  • Muller cells are living optical fibers in the vertebrate retina.

    abstract::Although biological cells are mostly transparent, they are phase objects that differ in shape and refractive index. Any image that is projected through layers of randomly oriented cells will normally be distorted by refraction, reflection, and scattering. Counterintuitively, the retina of the vertebrate eye is inverte...

    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.0611180104

    authors: Franze K,Grosche J,Skatchkov SN,Schinkinger S,Foja C,Schild D,Uckermann O,Travis K,Reichenbach A,Guck J

    更新日期:2007-05-15 00:00:00

  • Tn7 transposition: recognition of the attTn7 target sequence.

    abstract::The bacterial transposon Tn7 encodes two distinct but overlapping transposition pathways. tnsABC + tnsD promote transposition to a specific site, attTn7, while tnsABC + tnsE promote transposition to many other sites unrelated to attTn7. We have identified a tnsD-dependent DNA binding activity that specifically recogni...

    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.86.11.3958

    authors: Waddell CS,Craig NL

    更新日期:1989-06-01 00:00:00

  • Comparison of the peptide composition of two histocompatibility-2 alloantigens.

    abstract::The peptide composition of purified Histocompatibility-2 (H-2) reactive glycoprotein fragments from two murine strains allelic at the H-2 locus (H-2(b) and H-2(d)) were compared by a cellulose thin-layer peptide mapping micro technique. Approximately 70 per cent of the theoretical maximum number of peptides produced 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.65.3.691

    authors: Shimada A,Yamane K,Nathenson SG

    更新日期:1970-03-01 00:00:00

  • Cryptococcus neoformans interactions with amoebae suggest an explanation for its virulence and intracellular pathogenic strategy in macrophages.

    abstract::Cryptococcus neoformans (Cn) is a soil fungus that causes life-threatening meningitis in immunocompromised patients and is a facultative intracellular pathogen capable of replication inside macrophages. The mechanism by which environmental fungi acquire and maintain virulence for mammalian hosts is unknown. We hypothe...

    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.261418798

    authors: Steenbergen JN,Shuman HA,Casadevall A

    更新日期:2001-12-18 00:00:00