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  • 1.
    Chen, Siyi
    et al.
    Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, 1E Kent Ridge Rd,NUHS Tower Block,Level 10, Singapore 119228, Singapore..
    Larsson, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. ASTAR, Inst Mol & Cell Biol, 61 Biopolis Dr, Singapore 138673, Singapore..
    Robinson, Robert C.
    ASTAR, Inst Mol & Cell Biol, 61 Biopolis Dr, Singapore 138673, Singapore.;Natl Univ Singapore, Dept Biochem, Singapore 117597, Singapore.;Nanyang Technol Univ, NTU Inst Struct Biol, 59 Nanyang Dr, Singapore 636921, Singapore..
    Chen, Swaine L.
    Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, 1E Kent Ridge Rd,NUHS Tower Block,Level 10, Singapore 119228, Singapore.;Genome Inst Singapore, GERMS, 60 Biopolis St,Genome 02-01, Singapore 138672, Singapore.;Genome Inst Singapore, Infect Dis Grp, 60 Biopolis St,Genome 02-01, Singapore 138672, Singapore..
    Direct and convenient measurement of plasmid stability in lab and clinical isolates of E-coli2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 4788Article in journal (Refereed)
    Abstract [en]

    Plasmids are important mobile elements in bacteria, contributing to evolution, virulence, and antibiotic resistance. Natural plasmids are generally large and maintained at low copy number and thus prone to be lost. Therefore, dedicated plasmid maintenance systems have evolved, leading to plasmid loss rates as low as 1 per 107 divisions. These low rates complicate studies of plasmid loss, as traditional techniques for measuring plasmid loss are laborious and not quantitative. To overcome these limitations, we leveraged a stringent negative selection system to develop a method for performing direct, quantitative measurements of plasmid loss in E. coli. We applied our method to gain mechanistic insights into a heterologously reconstituted segregation system in lab strains and clinical isolates of E. coli. We also performed direct stability studies of a currently circulating resistance plasmid in a clinical isolate, strain EC958, which is a member of the rapidly expanding global ST131 E. coli clone. Our results establish the foundational assays required to screen for small molecules targeting plasmid stability, which could complement current strategies for reducing the spread of antibiotic resistance, complementing other strategies for treating antibiotic resistant bacteria.

  • 2.
    Chi, Celestine N.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Engström, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gianni, Stefano
    Larsson, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Jemth, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Two conserved residues govern the salt and pH dependencies of the binding reaction of a PDZ domain2006In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 281, no 48, p. 36811-36818Article in journal (Refereed)
    Abstract [en]

    PDZ domains are protein-protein interaction modules found in hundreds of human proteins. Their binding reactions are sensitive to variations in salt and pH but the basis of the respective dependence has not been clear. We investigated the binding reaction between PSD-95 PDZ3 and a peptide corresponding to a native ligand with protein engineering in conjunction with stopped-flow and equilibrium fluorimetry and found that the two conserved residues Arg-318 and His-372 were responsible for the salt and pH dependencies, respectively. The basis of the salt-dependent variation of the affinity was explored by mutating all charged residues in and around the peptide-binding pocket. Arg-318 was found to be crucial, as mutation to alanine obliterated the effect of chloride on the binding constants. The direct interaction of chloride with Arg-318 was demonstrated by time-resolved urea denaturation experiments, where the Arg-318 --> Ala mutant was less stabilized by addition of chloride as compared with wild-type PDZ3. We also demonstrated that protonation of His-372 was responsible for the increase of the equilibrium dissociation constant at low pH. Both chloride concentration and pH (during ischemia) vary in the postsynaptic density, where PSD-95 is present, and the physiological buffer conditions may thus modulate the interaction between PSD-95 and its ligands through binding of chloride and protons to the "molecular switches" Arg-318 and His-372, respectively.

  • 3.
    Chumnarnsilpa, Sakesit
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lee, Lin
    Nag, Shalini
    Kannan, Balakrishnan
    Larsson, Marten
    Burtnick, D
    Robinson, Robert C.
    The crystal structure of the C-terminus of adseverin reveals the actin-binding interface2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 33, p. 13719-13724Article in journal (Refereed)
    Abstract [en]

    Adseverin is a member of the calcium-regulated gelsolin superfamily of actin severing and capping proteins. Adseverin comprises 6 homologous domains (A1-A6), which share 60% identity with the 6 domains from gelsolin (G1-G6). Adseverin is truncated in comparison to gelsolin, lacking the C-terminal extension that masks the F-actin binding site in calcium-free gelsolin. Biochemical assays have indicated differences in the interaction of the C-terminal halves of adseverin and gelsolin with actin. Gelsolin contacts actin through a major site on G4 and a minor site on G6, whereas adseverin uses a site on A5. Here, we present the X-ray structure of the activated C-terminal half of adseverin (A4-A6). This structure is highly similar to that of the activated form of the C-terminal half of gelsolin (G4-G6), both in arrangement of domains and in the 3 bound calcium ions. Comparative analysis of the actin-binding surfaces observed in the G4-G6/actin structure suggests that adseverin in this conformation will also be able to interact with actin through A4 and A6, whereas the A5 surface is obscured. A single residue mutation in A4-A6 located at the predicted A4/actin interface completely abrogates actin sequestration. A model of calcium-free adseverin, constructed from the structure of gelsolin, predicts that in the absence of a gelsolin-like C-terminal extension the interaction between A2 and A6 provides the steric inhibition to prevent interaction with F-actin. We propose that calcium binding to the N terminus of adseverin dominates the activation process to expose the F-actin binding site on A2.

  • 4. Gianni, Stefano
    et al.
    Engström, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Larsson, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Calosci, Nicoletta
    Malatesta, Francesco
    Eklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Chi N, Celestine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. ETH.
    Travaglini-Allocatelli, Carlo
    Jemth, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    The kinetics of PDZ domain-ligand interactions and implications for the binding mechanism2005In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 280, no 41, p. 34805-34812Article in journal (Refereed)
    Abstract [en]

    PDZ domains are protein adapter modules present in a few hundred human proteins. They play important roles in scaffolding and signal transduction. PDZ domains usually bind to the C termini of their target proteins. To assess the binding mechanism of this interaction we have performed the first in-solution kinetic study for PDZ domains and peptides corresponding to target ligands. Both PDZ3 from postsynaptic density protein 95 and PDZ2 from protein tyrosine phosphatase L1 bind their respective target peptides through an apparent A + B --> A.B mechanism without rate-limiting conformational changes. But a mutant with a fluorescent probe (Trp) outside of the binding pocket suggests that slight changes in the structure take place upon binding in protein tyrosine phosphatase-L1 PDZ2. For PDZ3 from postsynaptic density protein 95 the pH dependence of the binding reaction is consistent with a one-step mechanism with one titratable group. The salt dependence of the interaction shows that the formation of electrostatic interactions is rate-limiting for the association reaction but not for dissociation of the complex.

  • 5.
    Hjälm, Göran
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Murray, Edward
    Crumley, Gregg
    Harazim, William
    Lundgren, Stefan
    Onyango, Isaac
    Ek, Bo
    Larsson, Mårten
    Juhlin, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Davis, Hughes
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Rask, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Morse, Buzzy
    Cloning and sequencing of human gp330, a Ca2+ -binding receptor with potential intracellular signaling properties1996In: European Journal of Biochemistry, ISSN 0014-2956, E-ISSN 1432-1033, Vol. 239, no 1, p. 132-137Article in journal (Refereed)
    Abstract [en]

    We present here the complete primary structure of human gp330, the human variant of the principal kidney autoantigen causing Heymann membranous glomerulonephritis in rats. The deduced 4655 amino acid residues give a calculated molecular mass of 519636 Da for the mature protein and consists of a probable 25-amino-acid N-terminal signal peptide sequence, an extracellular region of 4398 amino acids, a single transmembrane-spanning domain of 23 amino acids, and an intracellular C-terminal region of 209 amino acid residues. Three types of cysteine-rich repeats characteristic of the low density lipoprotein receptor (LDLR) superfamily are present in human gp330. In the extracellular region, there are a total of 36 LDLR ligand-binding repeats, comprising four distinct domains, 16 growth factor repeats separated by eight YWTD spacer regions, and one epidermal growth factor-like repeat. No consensus cleavage sequence for the processing endoprotease furin is detected in human gp330. The intracellular tail contains not only two copies of the F(X)NPXY coated-pit mediated internalization signal characteristic of LDLR superfamily members, but also intriguing and potentially functional motifs including several Src-homology 3 recognition motifs, one Src-homology 2 recognition motif for the p85 regulatory subunit of phosphatidylinositol 3-kinase, and additional sites for protein kinase C, casein kinase II and cAMP-/cGMP-dependent protein kinase. There is approximately 77% amino acid identity between human and rat gp330 with minor differences between the extracellular and intracellular regions. Recently gp330 has been implicated in Ca2+ regulation in the parathyroid, the placenta, and the renal tubule, but its overall physiological and pathological role still remains uncertain.

  • 6.
    Irobi, Edward
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Aguda, Adeleke, H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Larsson, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Guerin, Christophe
    Yin, Helen, L.
    Burtnick, Leslie, D.
    Blanchoin, Laurent
    Robinson, Robert, C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Structural basis of actin sequestration by thymosin β4: implications for WH2 proteins2004In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 23, no 18, p. 3599-608Article in journal (Refereed)
    Abstract [en]

    The WH2 (Wiscott-Aldridge syndrome protein homology domain 2) repeat is an actin interacting motif found in monomer sequestering and filament assembly proteins. We have stabilized the prototypical WH2 family member, thymosin-beta4 (Tbeta4), with respect to actin, by creating a hybrid between gelsolin domain 1 and the C-terminal half of Tbeta4 (G1-Tbeta4). This hybrid protein sequesters actin monomers, severs actin filaments and acts as a leaky barbed end cap. Here, we present the structure of the G1-Tbeta4:actin complex at 2 A resolution. The structure reveals that Tbeta4 sequesters by capping both ends of the actin monomer, and that exchange of actin between Tbeta4 and profilin is mediated by a minor overlap in binding sites. The structure implies that multiple WH2 motif-containing proteins will associate longitudinally with actin filaments. Finally, we discuss the role of the WH2 motif in arp2/3 activation.

  • 7.
    Jiang, Shimin
    et al.
    Agcy Sci Technol & Res, Inst Mol & Cell Biol, Singapore 138673, Singapore..
    Narita, Akihiro
    Nagoya Univ, Grad Sch Sci, Struct Biol Res Ctr, Chikusa Ku, Furo Cho, Nagoya, Aichi 4648602, Japan.;Nagoya Univ, Grad Sch Sci, Struct Biol Res Ctr, Div Biol Sci,Chikusa Ku, Furo Cho, Nagoya, Aichi 4648602, Japan.;Div Biol Sci, Furo Cho, Nagoya, Aichi 4648602, Japan.;Japan Sci & Technol Agcy, PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama 3320012, Japan..
    Popp, David
    Agcy Sci Technol & Res, Inst Mol & Cell Biol, Singapore 138673, Singapore..
    Ghoshdastider, Umesh
    Agcy Sci Technol & Res, Inst Mol & Cell Biol, Singapore 138673, Singapore..
    Lee, Lin Jie
    Agcy Sci Technol & Res, Inst Mol & Cell Biol, Singapore 138673, Singapore..
    Srinivasan, Ramanujam
    Natl Univ Singapore, Mechanobiol Inst, Singapore 117411, Singapore.;Natl Inst Sci Educ & Res, Bhubaneswar 751005, Orissa, India..
    Balasubramanian, Mohan K.
    Natl Univ Singapore, Mechanobiol Inst, Singapore 117411, Singapore.;Natl Univ Singapore, Temasek Life Sci Lab, Singapore 117604, Singapore.;Univ Warwick, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England..
    Oda, Toshiro
    Tokai Gakuin Univ, Gifu 5048511, Japan..
    Koh, Fujiet
    Agcy Sci Technol & Res, Inst Mol & Cell Biol, Singapore 138673, Singapore..
    Larsson, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Agcy Sci Technol & Res, Inst Mol & Cell Biol, Singapore 138673, Singapore..
    Robinson, Robert C.
    Agcy Sci Technol & Res, Inst Mol & Cell Biol, Singapore 138673, Singapore.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore 117597, Singapore..
    Novel actin filaments from Bacillus thuringiensis form nanotubules for plasmid DNA segregation2016In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 9, p. E1200-E1205Article in journal (Refereed)
    Abstract [en]

    Here we report the discovery of a bacterial DNA-segregating actin-like protein (BtParM) from Bacillus thuringiensis, which forms novel antiparallel, two-stranded, supercoiled, nonpolar helical filaments, as determined by electron microscopy. The BtParM filament features of supercoiling and forming antiparallel double-strands are unique within the actin fold superfamily, and entirely different to the straight, double-stranded, polar helical filaments of all other known ParMs and of eukaryotic F-actin. The BtParM polymers show dynamic assembly and subsequent disassembly in the presence of ATP. BtParR, the DNA-BtParM linking protein, stimulated ATP hydrolysis/phosphate release by BtParM and paired two supercoiled BtParM filaments to form a cylinder, comprised of four strands with inner and outer diameters of 57 angstrom and 145 angstrom, respectively. Thus, in this prokaryote, the actin fold has evolved to produce a filament system with comparable features to the eukaryotic chromosome-segregating microtubule.

  • 8.
    Larsson, Mårten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hjälm, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sakwe, Amos M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Engström, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Höglund, Anna-Stina
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Robinson, Robert C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sundberg, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rask, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Selective interaction of megalin with postsynaptic density-95 (PSD-95)-like membrane-associated guanylate kinase (MAGUK) proteins2003In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 373, no 2, p. 381-391Article in journal (Refereed)
    Abstract [en]

    Megalin is an integral membrane receptor belonging to the low-density lipoprotein receptor family. In addition to its role as an endocytotic receptor, megalin has also been proposed to have signalling functions. Using interaction cloning in yeast, we identified the membrane-associated guanylate kinase family member postsynaptic density-95 (PSD-95) as an interaction partner for megalin. PSD-95 and a truncated version of megalin were co-immunoprecipitated from HEK-293 cell lysates overexpressing the two proteins, which confirmed the interaction. The two proteins were found to be co-localized in these cells by confocal microscopy. Immunocytochemical studies showed that cells in the parathyroid, proximal tubuli of the kidney and placenta express both megalin and PSD-95. We found that the interaction between the two proteins is mediated by the binding of the C-terminus of megalin, which has a type I PSD-95/ Drosophila discs-large/zona occludens 1 (PDZ)-binding motif, to the PDZ2 domain of PSD-95. The PSD-95-like membrane-associated guanylate kinase ('MAGUK') family contains three additional members: PSD-93, synapse-associated protein 97 (SAP97) and SAP102. We detected these proteins, apart from SAP102, in parathyroid chief cells, a cell type having a marked expression of megalin. The PDZ2 domains of PSD-93 and SAP102 were also shown to interact with megalin, whereas no interaction was detected for SAP97. The SAP97 PDZ2 domain differed at four positions from the other members of the PSD-95 subfamily. One of these residues was Thr(389), located in the alphaB-helix and part of the hydrophobic pocket of the PDZ2 domain. Surface plasmon resonance experiments revealed that mutation of SAP97 Thr(389) to alanine, as with the other PSD-95-like membrane-associated guanylate kinases, induced binding to megalin.

  • 9.
    Larsson, Mårten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wicher, Grzegorz
    Thuveson, Maria
    Hallberg, Mathias
    Melhus, Håkan
    Engström, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Jemth, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Aldskogius, Håkan
    Rask, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Low-density lipoprotein receptor-related protein (LRP)-2/megalin plays a role as a receptor for retinol-binding protein on retina pigment epithelial cells of the eye.Manuscript (Other academic)
    Abstract
  • 10. Nag, Shalini
    et al.
    Larsson, Mårten
    Institute of Molecular and Cell Biology, A*STAR, Singapore.
    Robinson, Robert C
    Burtnick, Leslie D
    Gelsolin: the tail of a molecular gymnast2013In: Cytoskeleton (Hoboken, N.J.), ISSN 1949-3592, Vol. 70, no 7, p. 360-384Article, review/survey (Refereed)
    Abstract [en]

    Gelsolin superfamily members are Ca(2+) -dependent, multidomain regulators of the actin cytoskeleton. Calcium binding activates gelsolin by inducing molecular gymnastics (large-scale conformational changes) that expose actin interaction surfaces by releasing a series of latches. A specialized tail latch has distinguished gelsolin within the superfamily. Active gelsolin exhibits actin filament severing and capping, and actin monomer sequestering activities. Here, we analyze a combination of sequence, structural, biophysical and biochemical data to assess whether the molecular plasticity, regulation and actin-related properties of gelsolin are also present in other superfamily members. We conclude that all members of the superfamily will be able to transition between a compact conformation and a more open form, and that most of these open forms will interact with actin. Supervillin, which lacks the severing domain 1 and the F-actin binding-site on domain 2, is the clear exception. Eight calcium-binding sites are absolutely conserved in gelsolin, adseverin, advillin and villin, and compromised to increasing degrees in CapG, villin-like protein, supervillin and flightless I. Advillin, villin and supervillin each contain a potential tail latch, which is absent from CapG, adseverin and flightless I, and ambiguous in villin-like protein. Thus, calcium regulation will vary across the superfamily. Potential novel isoforms of the superfamily suggest complex regulation at the gene, transcript and protein levels. We review animal, clinical and cellular data that illuminate how the regulation of molecular flexibility in gelsolin-like proteins permits cells to exploit the force generated from actin polymerization to drive processes such as cell movement in health and disease.

  • 11.
    Popp, David
    et al.
    ASTAR, Inst Mol & Cell Biol, Biopolis, Singapore 138673, Singapore..
    Loh, N. Duane
    Natl Univ Singapore, Dept Phys, Singapore 117557, Singapore.;Natl Univ Singapore, Ctr BioImaging Sci, Singapore 117546, Singapore..
    Zorgati, Habiba
    ASTAR, Inst Mol & Cell Biol, Biopolis, Singapore 138673, Singapore.;Natl Univ Singapore, Dept Biochem, Singapore 117597, Singapore..
    Ghoshdastider, Umesh
    ASTAR, Inst Mol & Cell Biol, Biopolis, Singapore 138673, Singapore..
    Liow, Lu Ting
    Natl Univ Singapore, Dept Med, Singapore 119074, Singapore..
    Ivanova, Magdalena I.
    Univ Michigan, Dept Neurol, 109 Zina Pitcher Pl, Ann Arbor, MI 48109 USA..
    Larsson, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. ASTAR, Inst Mol & Cell Biol, Biopolis, Singapore 138673, Singapore.
    DePonte, Daniel P.
    SLAC Natl Accelerator Lab, Linac Coherent Light Source, 2575 Sand Hill Rd, Menlo Pk, CA 94025 USA..
    Bean, Richard
    DESY, Ctr Free Electron Laser Sci, Notkestr 85, D-22607 Hamburg, Germany.;European XFEL GmbH, D-22761 Hamburg, Germany..
    Beyerlein, Kenneth R.
    DESY, Ctr Free Electron Laser Sci, Notkestr 85, D-22607 Hamburg, Germany..
    Gati, Cornelius
    DESY, Ctr Free Electron Laser Sci, Notkestr 85, D-22607 Hamburg, Germany..
    Oberthuer, Dominik
    DESY, Ctr Free Electron Laser Sci, Notkestr 85, D-22607 Hamburg, Germany.;Univ Hamburg, Inst Biochem & Mol Biol, D-22607 Hamburg, Germany..
    Arnlund, David
    Univ Gothenburg, Dept Chem & Mol Biol, S-40530 Gothenburg, Sweden..
    Branden, Gisela
    Univ Gothenburg, Dept Chem & Mol Biol, S-40530 Gothenburg, Sweden..
    Berntsen, Peter
    Univ Gothenburg, Dept Chem & Mol Biol, S-40530 Gothenburg, Sweden..
    Cascio, Duilio
    Univ Calif Los Angeles, Howard Hughes Med Inst, Los Angeles, CA 90095 USA..
    Chavas, Leonard M. G.
    DESY, Ctr Free Electron Laser Sci, Notkestr 85, D-22607 Hamburg, Germany..
    Chen, Joe P. J.
    Univ Canterbury, Computat Imaging Grp, Dept Elect & Comp Engn, Christchurch, New Zealand.;Arizona State Univ, Dept Phys, Tempe, AZ 85287 USA..
    Ding, Ke
    ASTAR, Inst Mol & Cell Biol, Biopolis, Singapore 138673, Singapore..
    Fleckenstein, Holger
    DESY, Ctr Free Electron Laser Sci, Notkestr 85, D-22607 Hamburg, Germany..
    Gumprecht, Lars
    DESY, Ctr Free Electron Laser Sci, Notkestr 85, D-22607 Hamburg, Germany..
    Harimoorthy, Rajiv
    Univ Gothenburg, Dept Chem & Mol Biol, S-40530 Gothenburg, Sweden..
    Mossou, Estelle
    Inst Laue Langevin, F-38000 Grenoble, France.;Keele Univ, EPSAM ISTM, Keele ST5 5BG, Staffs, England..
    Sawaya, Michael R.
    Univ Calif Los Angeles, Howard Hughes Med Inst, Los Angeles, CA 90095 USA..
    Brewster, Aaron S.
    Lawrence Berkeley Natl Lab, Phys Biosci Div, Berkeley, CA 94720 USA..
    Hattne, Johan
    Lawrence Berkeley Natl Lab, Phys Biosci Div, Berkeley, CA 94720 USA.;Howard Hughes Med Inst, Janelia Res Campus,19700 Helix Dr, Ashburn, VA 20147 USA..
    Sauter, Nicholas K.
    Lawrence Berkeley Natl Lab, Phys Biosci Div, Berkeley, CA 94720 USA..
    Seibert, Marvin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics.
    Seuring, Carolin
    DESY, Ctr Free Electron Laser Sci, Notkestr 85, D-22607 Hamburg, Germany..
    Stellato, Francesco
    DESY, Ctr Free Electron Laser Sci, Notkestr 85, D-22607 Hamburg, Germany..
    Tilp, Thomas
    DESY, Ctr Free Electron Laser Sci, Notkestr 85, D-22607 Hamburg, Germany..
    Eisenberg, David S.
    Univ Calif Los Angeles, Howard Hughes Med Inst, Los Angeles, CA 90095 USA..
    Messerschmidt, Marc
    SLAC Natl Accelerator Lab, Linac Coherent Light Source, 2575 Sand Hill Rd, Menlo Pk, CA 94025 USA..
    Williams, Garth J.
    SLAC Natl Accelerator Lab, Linac Coherent Light Source, 2575 Sand Hill Rd, Menlo Pk, CA 94025 USA..
    Koglin, Jason E.
    SLAC Natl Accelerator Lab, Linac Coherent Light Source, 2575 Sand Hill Rd, Menlo Pk, CA 94025 USA..
    Makowski, Lee
    Northeastern Univ, Dept Bioengn, 360 Huntington Ave, Boston, MA 02115 USA..
    Millane, Rick P.
    Univ Canterbury, Computat Imaging Grp, Dept Elect & Comp Engn, Christchurch, New Zealand..
    Forsyth, Trevor
    Inst Laue Langevin, F-38000 Grenoble, France.;Keele Univ, EPSAM ISTM, Keele ST5 5BG, Staffs, England..
    Boutet, Sebastien
    SLAC Natl Accelerator Lab, Linac Coherent Light Source, 2575 Sand Hill Rd, Menlo Pk, CA 94025 USA..
    White, Thomas A.
    DESY, Ctr Free Electron Laser Sci, Notkestr 85, D-22607 Hamburg, Germany..
    Barty, Anton
    DESY, Ctr Free Electron Laser Sci, Notkestr 85, D-22607 Hamburg, Germany..
    Chapman, Henry
    DESY, Ctr Free Electron Laser Sci, Notkestr 85, D-22607 Hamburg, Germany.;Univ Hamburg, Dept Phys, Luruper Chaussee 149, D-22607 Hamburg, Germany..
    Chen, Swaine L.
    Natl Univ Singapore, Dept Med, Singapore 119074, Singapore.;ASTAR, Biopolis, Genome Inst Singapore, Singapore 138672, Singapore..
    Liang, Mengning
    SLAC Natl Accelerator Lab, Linac Coherent Light Source, 2575 Sand Hill Rd, Menlo Pk, CA 94025 USA.;DESY, Ctr Free Electron Laser Sci, Notkestr 85, D-22607 Hamburg, Germany..
    Neutze, Richard
    Univ Gothenburg, Dept Chem & Mol Biol, S-40530 Gothenburg, Sweden..
    Robinson, Robert C.
    ASTAR, Inst Mol & Cell Biol, Biopolis, Singapore 138673, Singapore.;Natl Univ Singapore, Dept Biochem, Singapore 117597, Singapore.;Okayama Univ, Res Inst Interdisciplinary Sci, Okayama 7008530, Japan..
    Flow-aligned, single-shot fiber diffraction using a femtosecond X-ray free-electron laser2017In: CYTOSKELETON, ISSN 1949-3584, Vol. 74, no 12, p. 472-481Article in journal (Refereed)
    Abstract [en]

    A major goal for X-ray free-electron laser (XFEL) based science is to elucidate structures of biological molecules without the need for crystals. Filament systems may provide some of the first single macromolecular structures elucidated by XFEL radiation, since they contain one-dimensional translational symmetry and thereby occupy the diffraction intensity region between the extremes of crystals and single molecules. Here, we demonstrate flow alignment of as few as 100 filaments (Escherichia coli pili, F-actin, and amyloid fibrils), which when intersected by femtosecond X-ray pulses result in diffraction patterns similar to those obtained from classical fiber diffraction studies. We also determine that F-actin can be flow-aligned to a disorientation of approximately 5 degrees. Using this XFEL-based technique, we determine that gelsolin amyloids are comprised of stacked -strands running perpendicular to the filament axis, and that a range of order from fibrillar to crystalline is discernable for individual -synuclein amyloids.

  • 12.
    Sakwe, Amos M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Engström, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Larsson, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rask, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Biosynthesis and secretion of parathyroid hormone are sensitive to proteasome inhibitors in dispersed bovine parathyroid cells2002In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 277, no 20, p. 17687-17695Article in journal (Refereed)
    Abstract [en]

    Preproparathyroid hormone (prepro-PTH) is one of the proteins abundantly synthesized by parathyroid chief cells; yet under normal growth conditions, little or no prepro-PTH can be detected in these cells. Although this may be attributed to effective cotranslational translocation and proteolytic processing, proteasome-mediated degradation of PTH precursors may be important in the regulation of the levels of these precursors and hence PTH secretion. The effects of N-acetyl-Leu-Leu-norleucinal, N-acetyl-Leu-Leu-methional, carbobenzoxy-Leu-Leu-leucinal (MG132), benzyloxycarbonyl-Ile-Glu(t-butyl)-Ala-leucinal (proteasome inhibitor I), and lactacystin on the biosynthesis and secretion of PTH were examined in dispersed bovine parathyroid cells. We demonstrate that treatment of these cells with proteasome inhibitors caused the accumulation of prepro-PTH and pro-PTH. Compared with mock-treated cells, the processing of pro-PTH to PTH was delayed, and the secretion of intact PTH decreased in proteasome inhibitor-treated cells. Relieving the inhibition of the proteasome by chasing MG132-treated cells in medium without the inhibitor led to the rapid disappearance of the accumulated prepro-PTH, and the rate of PTH secretion was restored to levels comparable to those in mock-treated cells. Furthermore, overexpression of the Hsp70 family of molecular chaperones was observed in proteasome inhibitor-treated cells, and we show that PTH/PTH precursors interact with these molecular chaperones. These data suggest the involvement of parathyroid cell proteasomes in the quality control of PTH biosynthesis.

  • 13.
    Sakwe, Amos M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Larsson, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rask, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Involvement of protein kinase C-alpha and -epsilon in extracellular Ca(2+) signalling mediated by the calcium sensing receptor2004In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 297, no 2, p. 560-573Article in journal (Refereed)
    Abstract [en]

    The sensing of extracellular Ca(2+) concentration ([Ca(2+)](o)) and modulation of cellular processes associated with acute or sustained changes in [Ca(2+)](o) are cell-type specific and mediated by the calcium sensing receptor (CaR). [Ca(2+)](o) signalling requires protein kinase C (PKC), but the identity and role of PKC isoforms in CaR-mediated responses remain unclear. Here we show that high [Ca(2+)](o) activated PKC-alpha and PKC- in parathyroid cells and in human embryonic kidney (HEK293) cells overexpressing the CaR (HEK-CaR) and that this response correlated with the CaR-dependent activation of mitogen-activated protein kinases ERK1/2. Activation of ERK1/2 by acute high [Ca(2+)](o) required influx of Ca(2+)through Ni(2+)-sensitive Ca(2+)channels and phosphatidylinositol-dependent phospholipase C-beta activity. Inhibition of PKC by co-expression of dominant-negative (DN) mutants of PKC-alpha or - with the CaR attenuated sustained ERK1/2 activation. Overexpression of a PKC phosphorylation site (T888A) mutant CaR in HEK293 cells showed that this site was important for ERK1/2 activation at high [Ca(2+)](o). Activation of ERK1/2 by high [Ca(2+)](o) was not necessary for the [Ca(2+)](o)-regulated secretion of parathyroid hormone (PTH) in dispersed bovine parathyroid cells. These data suggest that the CaR-mediated [Ca(2+)](o) signal leading to regulated PTH secretion that requires diacylglycerol-responsive PKC isoforms is not mediated via the ERK pathway.

  • 14.
    Thalmann, Doreen Schwochow
    et al.
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden.;Univ Paris Saclay, GABI, INRA, AgroParisTech, F-78350 Jouy En Josas, France..
    Ring, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Sundström, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cao, Xiaofang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larsson, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kerje, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Höglund, Andrey
    Linkoping Univ, AVIAN Behav Genom & Physiol Grp, IFM Biol, Linkoping, Sweden..
    Fogelholm, Jesper
    Linkoping Univ, AVIAN Behav Genom & Physiol Grp, IFM Biol, Linkoping, Sweden..
    Wright, Dominic
    Linkoping Univ, AVIAN Behav Genom & Physiol Grp, IFM Biol, Linkoping, Sweden..
    Jemth, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Bed'Hom, Bertrand
    Univ Paris Saclay, GABI, INRA, AgroParisTech, F-78350 Jouy En Josas, France..
    Dorshorst, Ben
    Virginia Tech, Dept Anim & Poultry Sci, Blacksburg, VA USA..
    Tixier-Boichard, Michele
    Univ Paris Saclay, GABI, INRA, AgroParisTech, F-78350 Jouy En Josas, France..
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden.;Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Integrat Biosci, College Stn, TX 77843 USA..
    The evolution of Sex-linked barring alleles in chickens involves both regulatory and coding changes in CDKN2A2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 4, article id e1006665Article in journal (Refereed)
    Abstract [en]

    Sex-linked barring is a fascinating plumage pattern in chickens recently shown to be associated with two non-coding and two missense mutations affecting the ARF transcript at the CDKN2A tumor suppressor locus. It however remained a mystery whether all four mutations are indeed causative and how they contribute to the barring phenotype. Here, we show that Sex-linked barring is genetically heterogeneous, and that the mutations form three functionally different variant alleles. The B0 allele carries only the two non-coding changes and is associated with the most dilute barring pattern, whereas the B1 and B2 alleles carry both the two non-coding changes and one each of the two missense mutations causing the Sex-linked barring and Sex-linked dilution phenotypes, respectively. The data are consistent with evolution of alleles where the non-coding changes occurred first followed by the two missense mutations that resulted in a phenotype more appealing to humans. We show that one or both of the non-coding changes are cis-regulatory mutations causing a higher CDKN2A expression, whereas the missense mutations reduce the ability of ARF to interact with MDM2. Caspase assays for all genotypes revealed no apoptotic events and our results are consistent with a recent study indicating that the loss of melanocyte progenitors in Sex-linked barring in chicken is caused by premature differentiation and not apoptosis. Our results show that CDKN2A is a major locus driving the differentiation of avian melanocytes in a temporal and spatial manner.

  • 15.
    Wicher, Grzegorz
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Larsson, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Fex Svenningsen, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Gyllencreutz, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Rask, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Low density lipoprotein-related protein-2/megalin is expressed in oligodendrocytes in the mouse spinal cord white matter2006In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 83, no 5, p. 864-873Article in journal (Refereed)
    Abstract [en]

    Lipoprotein receptor-related protein-2 (LRP2)/megalin is a member of the low density lipoprotein receptor (LDLR) family, and is essential in absorptive epithelia for endocytosis of lipoproteins, low molecular weight proteins, cholesterol and vitamins, as well as in cellular signaling. Previous studies have shown megalin expression in ependymal cells and choroid plexus. We have investigated megalin expression in the spinal cord of postnatal mice with immunohistochemistry and immunoblot. Antibodies recognizing either the cytoplasmic tail (MM6) or the extracellular domain (E11) of megalin labeled oligodendrocytes in the spinal cord white matter, in parallel with myelination. MM6 antibodies, predominantly labeled the nuclei, whereas E11 antibodies labeled the cytoplasm of these cells. MM6 antibodies labeled also nuclei of oligodendrocytes cultured from embryonic mouse spinal cord. Immunoblots of spinal cord showed intact megalin, as well as its carboxyterminal fragment, the part remaining after shedding of the extracellular domain of megalin. Megalin-immunoreactive oligodendrocytes also expressed presenilin 1, an enzyme responsible for gamma-secretase mediated endodomain cleavage. These findings show that spinal cord oligodendrocytes are phenotypically different from those in the brain, and indicate that megalin translocates signals from the cell membrane to the nucleus of oligodendrocytes during the formation and maintenance of myelin of long spinal cord pathways.

  • 16.
    Wicher, Grzegorz
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Larsson, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rask, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Aldskogius, Hakan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Low-density lipoprotein receptor-related protein (LRP)-2/megalin is transiently expressed in a subpopulation of neural progenitors in the embryonic mouse spinal cord2005In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 492, no 2, p. 123-131Article in journal (Refereed)
    Abstract [en]

    The lipoprotein receptor LRP2/megalin is expressed by absorptive epithelia and involved in receptor-mediated endocytosis of a wide range of ligands. Megalin is expressed in the neuroepithelium during central nervous system (CNS) development. Mice with homozygous deletions of the megalin gene show severe forebrain abnormalities. The possible role of megalin in the developing spinal cord, however, is unknown. Here we examined the spatial and temporal expression pattern of megalin in the embryonic mouse spinal cord using an antibody that specifically recognizes the cytoplasmic part of the megalin molecule. In line with published data, we show expression of megalin in ependymal cells of the central canal from embryonic day (E)11 until birth. In addition, from E11 until E15 a population of cells was found in the dorsal part of the developing spinal cord strongly immunoreactive against megalin. Double labeling showed that most of these cells express vimentin, a marker for immature astrocytes and radial glia, but not brain lipid binding protein (BLBP), a marker for radial glial cells, or glial fibrillary acidic protein (GFAP), a marker for mature astrocytes. These findings indicate that the majority of the megalin-positive cells are astroglial precursors. Megalin immunoreactivity was mainly localized in the nuclei of these cells, suggesting that the cytoplasmic part of the megalin molecule can be cleaved following ligand binding and translocated to the nucleus to act as a transcription factor or regulate other transcription factors. These findings suggest that megalin has a crucial role in the development of astrocytes of the spinal cord.

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