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  • 1.
    Dhanraj, Santhosh
    et al.
    Univ Toronto, Inst Med Sci, Toronto, ON, Canada.;Hosp Sick Children, Genet & Genome Biol Program, Toronto, ON, Canada..
    Gunja, Sethu Madhava Rao
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Deveau, Adam P.
    IWK Hlth Ctr, Dept Pediat, Halifax, NS, Canada..
    Nissbeck, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Boonyawat, Boonchai
    Hosp Sick Children, Genet & Genome Biol Program, Toronto, ON, Canada..
    Coombs, Andrew J.
    IWK Hlth Ctr, Dept Pediat, Halifax, NS, Canada..
    Renieri, Alessandra
    Univ Siena, Med Genet, I-53100 Siena, Italy..
    Mucciolo, Mafalda
    Univ Siena, Med Genet, I-53100 Siena, Italy..
    Marozza, Annabella
    Univ Siena, Med Genet, I-53100 Siena, Italy..
    Buoni, Sabrina
    Univ Siena, Pediat Neurol, Siena, Italy..
    Turner, Lesley
    Mem Univ Newfoundland, Discipline Genet, St John, NF, Canada..
    Li, Hongbing
    Hosp Sick Children, Genet & Genome Biol Program, Toronto, ON, Canada..
    Jarrar, Ameer
    IWK Hlth Ctr, Dept Pediat, Halifax, NS, Canada..
    Sabanayagam, Mathura
    Hosp Sick Children, Genet & Genome Biol Program, Toronto, ON, Canada..
    Kirby, Melanie
    Hosp Sick Children, Dept Pediat, Div Hematol Oncol, Toronto, ON M5G 1X8, Canada..
    Shago, Mary
    Hosp Sick Children, Dept Paediat, Lab Med, Cytogenet Lab, Toronto, ON, Canada..
    Pinto, Dalila
    Mt Sinai Sch Med, Mindich Child Hlth & Dev Inst, Seaver Autism Ctr, Dept Psychiat, New York, NY USA.;Mt Sinai Sch Med, Mindich Child Hlth & Dev Inst, Seaver Autism Ctr, Dept Genet & Genom Sci, New York, NY USA..
    Berman, Jason N.
    Dalhousie Univ, IWK Hlth Ctr, Pediat, Microbiol & Immunol, Halifax, NS, Canada..
    Scherer, Stephen W.
    Hosp Sick Children, Genet & Genome Biol Program, Toronto, ON, Canada..
    Virtanen, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Dror, Yigal
    Univ Toronto, Inst Med Sci, Toronto, ON, Canada.;Hosp Sick Children, Genet & Genome Biol Program, Toronto, ON, Canada.;Hosp Sick Children, Dept Pediat, Div Hematol Oncol, Marrow Failure & Myelodysplasia Program, Toronto, ON M5G 1X8, Canada..
    Bone Marrow Failure and Developmental Delay Caused By Mutations in Poly(A)-Specific Ribonuclease2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 2.
    Dhanraj, Santhosh
    et al.
    Hosp Sick Children, Res Inst, Genet & Genome Biol Program, Toronto, ON M5G 1X8, Canada.;Univ Toronto, Inst Med Sci, Toronto, ON, Canada..
    Gunja, Sethu Madhava Rao
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Deveau, Adam P.
    Dalhousie Univ, Dept Microbiol & Immunol, Halifax, NS, Canada..
    Nissbeck, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Boonyawat, Boonchai
    Hosp Sick Children, Res Inst, Genet & Genome Biol Program, Toronto, ON M5G 1X8, Canada.;Hosp Sick Children, Dept Paediat, Toronto, ON M5G 1X8, Canada..
    Coombs, Andrew J.
    IWK Hlth Ctr, Dept Pediat, Halifax, NS, Canada.;Dalhousie Univ, Halifax, NS, Canada..
    Renieri, Alessandra
    Univ Siena, Dept Med Genet, I-53100 Siena, Italy..
    Mucciolo, Mafalda
    Azienda Osped Univ Senese, Genet Med, Siena, Italy..
    Marozza, Annabella
    Azienda Osped Univ Senese, Genet Med, Siena, Italy..
    Buoni, Sabrina
    Univ Senese, Azienda Osped, Neuropsichiat Infantile, Siena, Italy..
    Turner, Lesley
    Mem Univ Newfoundland, Dept Discipline Genet, St John, NF, Canada..
    Li, Hongbing
    Hosp Sick Children, Res Inst, Genet & Genome Biol Program, Toronto, ON M5G 1X8, Canada..
    Jarrar, Ameer
    IWK Hlth Ctr, Dept Pediat, Halifax, NS, Canada.;Dalhousie Univ, Halifax, NS, Canada..
    Sabanayagam, Mathura
    Hosp Sick Children, Res Inst, Genet & Genome Biol Program, Toronto, ON M5G 1X8, Canada..
    Kirby, Melanie
    Shago, Mary
    Hosp Sick Children, Dept Paediat Lab Med, Toronto, ON M5G 1X8, Canada..
    Pinto, Dalila
    Hosp Sick Children, Res Inst, Genet & Genome Biol Program, Toronto, ON M5G 1X8, Canada.;Mt Sinai Sch Med, Mindich Child Hlth & Dev Inst, Seaver Autism Ctr, Dept Psychiat & Genet, New York, NY USA.;Mt Sinai Sch Med, Mindich Child Hlth & Dev Inst, Seaver Autism Ctr, Dept Genom Sci, New York, NY USA..
    Berman, Jason N.
    IWK Hlth Ctr, Dept Pediat, Halifax, NS, Canada.;Dalhousie Univ, Halifax, NS, Canada..
    Scherer, Stephen W.
    Hosp Sick Children, Res Inst, Genet & Genome Biol Program, Toronto, ON M5G 1X8, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada..
    Virtanen, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Dror, Yigal
    Hosp Sick Children, Res Inst, Genet & Genome Biol Program, Toronto, ON M5G 1X8, Canada.;Univ Toronto, Inst Med Sci, Toronto, ON, Canada.;Hosp Sick Children, Dept Paediat, Toronto, ON M5G 1X8, Canada..
    Bone marrow failure and developmental delay caused by mutations in poly(A)-specific ribonuclease (PARN)2015In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 52, no 11, p. 738-748Article in journal (Refereed)
    Abstract [en]

    Background Deadenylation regulates RNA function and fate. Poly(A)-specific ribonuclease (PARN) is a deadenylase that processes mRNAs and non-coding RNA. Little is known about the biological significance of germline mutations in PARN. Methods We identified mutations in PARN in patients with haematological and neurological manifestations. Genomic, biochemical and knockdown experiments in human marrow cells and in zebrafish have been performed to clarify the role of PARN in the human disease. Results We identified large monoallelic deletions in PARN in four patients with developmental delay or mental illness. One patient in particular had a severe neurological phenotype, central hypomyelination and bone marrow failure. This patient had an additional missense mutation on the non-deleted allele and severely reduced PARN protein and deadenylation activity. Cells from this patient had impaired oligoadenylation of specific H/ACA box small nucleolar RNAs. Importantly, PARN-deficient patient cells manifested short telomeres and an aberrant ribosome profile similar to those described in some variants of dyskeratosis congenita. Knocking down PARN in human marrow cells and zebrafish impaired haematopoiesis, providing further evidence for a causal link with the human disease. Conclusions Large monoallelic mutations of PARN can cause developmental/mental illness. Biallelic PARN mutations cause severe bone marrow failure and central hypomyelination.

  • 3.
    Kirsebom, Leif A
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Cell Biology. Mikrobiologi.
    Virtanen, Anders
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Cell Biology. Molekylär Cellbiologi.
    Mikkelsen, Nils-Egil
    Inst Molekylärbiologi SLU.
    Aminoglycoside interactions with RNAs and nucleases2006In: RNA towards medicine, Springer Verlag , 2006, p. 23-Chapter in book (Other scientific)
  • 4.
    Kirsebom, Leif
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Cell Biology.
    Virtanen, Anders
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Cell Biology. Molekylär cellbiologi.
    Inhibition of RNase P processing2001In: RNA-Binding Antibiotics, Eurekah.com, Austin, TX, USA and Landes Bioscences, Georgetown, TX, USA , 2001, p. 56-72Chapter in book (Other scientific)
  • 5.
    Kyriakopoulou, Christina B.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Nordvarg, Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Virtanen, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    A novel nuclear human poly(A) polymerase (PAP), PAPγ2001In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 276, no 36, p. 33504-33511Article in journal (Refereed)
    Abstract [en]

    Poly(A) polymerase (PAP) is present in multiple forms in mammalian cells and tissues. Here we show that the 90-kDa isoform is the product of the gene PAPOLG, which is distinct from the previously identified genes for poly(A) polymerases. The 90-kDa isoform is referred to as human PAPγ (hsPAPγ). hsPAPγ shares 60% identity to human PAPII (hsPAPII) at the amino acid level. hsPAPγ exhibits fundamental properties of a bona fidepoly(A) polymerase, specificity for ATP, and cleavage and polyadenylation specificity factor/hexanucleotide-dependent polyadenylation activity. The catalytic parameters indicate similar catalytic efficiency to that of hsPAPII. Mutational analysis and sequence comparison revealed that hsPAPγ and hsPAPII have similar organization of structural and functional domains. hsPAPγ contains a U1A protein-interacting region in its C terminus, and PAPγ activity can be inhibited, as hsPAPII, by the U1A protein. hsPAPγ is restricted to the nucleus as revealed by in situ staining and by transfection experiments. Based on this and previous studies, it is obvious that multiple isoforms of PAP are generated by three distinct mechanisms: gene duplication, alternative RNA processing, and post-translational modification. The exclusive nuclear localization of hsPAPγ establishes that multiple forms of PAP are unevenly distributed in the cell, implying specialized roles for the various isoforms.

  • 6.
    Liljeruhm, Josefine
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.
    Funk, Saskia K.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Tietscher, Sandra
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Edlund, Anders D.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala Univ, iGEM Uppsala, Uppsala, Sweden.
    Jamal, Sabri
    Uppsala Univ, iGEM Uppsala, Uppsala, Sweden.
    Yuen, Pikkei
    Uppsala Univ, iGEM Uppsala, Uppsala, Sweden.
    Dyrhage, Karl
    Uppsala Univ, iGEM Uppsala, Uppsala, Sweden.
    Gynnå, Arvid H.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology. Uppsala Univ, iGEM Uppsala, Uppsala, Sweden.
    Ivermark, Katarina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Lövgren, Jessica
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Törnblom, Viktor
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Virtanen, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Lundin, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala Univ, iGEM Uppsala, Uppsala, Sweden.
    Wistand-Yuen, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Forster, Anthony C.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Engineering a palette of eukaryotic chromoproteins for bacterial synthetic biology2018In: Journal of Biological Engineering, ISSN 1754-1611, E-ISSN 1754-1611, Vol. 12, article id 8Article in journal (Refereed)
    Abstract [en]

    Background: Coral reefs are colored by eukaryotic chromoproteins (CPs) that are homologous to green fluorescent protein. CPs differ from fluorescent proteins (FPs) by intensely absorbing visible light to give strong colors in ambient light. This endows CPs with certain advantages over FPs, such as instrument-free detection uncomplicated by ultra-violet light damage or background fluorescence, efficient Forster resonance energy transfer (FRET) quenching, and photoacoustic imaging. Thus, CPs have found utility as genetic markers and in teaching, and are attractive for potential cell biosensor applications in the field. Most near-term applications of CPs require expression in a different domain of life: bacteria. However, it is unclear which of the eukaryotic CP genes might be suitable and how best to assay them.

    Results: Here, taking advantage of codon optimization programs in 12 cases, we engineered 14 CP sequences (meffRed, eforRed, asPink, spisPink, scOrange, fwYellow, amilGFP, amajLime, cjBlue, mefiBlue, aeBlue, amilCP, tsPurple and gfasPurple) into a palette of Escherichia coil BioBrick plasmids. BioBricks comply with synthetic biology's most widely used, simplified, cloning standard. Differences in color intensities, maturation times and fitness costs of expression were compared under the same conditions, and visible readout of gene expression was quantitated. A surprisingly large variation in cellular fitness costs was found, resulting in loss of color in some overnight liquid cultures of certain high-copy-plasmid-borne CPs, and cautioning the use of multiple CPs as markers in competition assays. We solved these two problems by integrating pairs of these genes into the chromosome and by engineering versions of the same CP with very different colors.

    Conclusion: Availability of 14 engineered CP genes compared in E coil, together with chromosomal mutants suitable for competition assays, should simplify and expand CP study and applications. There was no single plasmid-borne CP that combined all of the most desirable features of intense color, fast maturation and low fitness cost, so this study should help direct future engineering efforts.

  • 7.
    Martinez, J
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Ren, Yan-Guo
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Hellman, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Aström, J
    Amersham Pharmacia Biotech.
    Virtanen, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    A 54-kDa fragment of the Poly(A)-specific ribonuclease is an oligomeric, processive, and cap-interacting Poly(A)-specific 3' exonuclease.2000In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 275, no 31, p. 24222-24230Article in journal (Refereed)
    Abstract [en]

    We have previously identified a HeLa cell 3' exonuclease specific for degrading poly(A) tails ofmRNAs, Here we report on the purification and identification of a calf thymus 54-kDa polypeptide associated witha similar 3' exonuclease activity. The 54-kDa polypeptide was shown to be a fragment of the poly(A)-specificribonuclease 74-kDa polypeptide. The native molecular mass of the nuclease activity was estimated to be 180-220 kDa, Protein/protein cross-linking revealed an oligomeric structure, most likely consisting of three subunits.The purified nuclease activity released 5'-AMP as the reaction product and degraded poly(A) in a highlyprocessive fashion. The activity required monovalent cations and was dependent on divalent metal ions. TheRNA substrate requirement was investigated, and it was found that the nuclease was highly poly(A)-specific and that only 3' end-located poly(A) was degraded by the activity. RNA substrates capped with m(7)G(5')ppp(5')G were more efficiently degraded than noncapped RNA substrates. Addition of free m7G(5')ppp(5')G cap analogue inhibited poly(A) degradation in vitro, suggesting a functional link between the RNA 5' end cap structure andpoly(A) degradation at the 3' end of the RNA.

  • 8.
    Niedzwiecka, Anna
    et al.
    Polish Acad Sci, Inst Phys, Phys Biol Lab, PL-02668 Warsaw, Poland..
    Nilsson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. RIKEN, Brain Sci Inst, Wako, Saitama, Japan.;Karolinska Inst, Dept Neurobiol Care Sci & Soc, SE-14157 Huddinge, Sweden..
    Worch, Remigiusz
    Polish Acad Sci, Inst Phys, Phys Biol Lab, PL-02668 Warsaw, Poland..
    Stepinski, Janusz
    Univ Warsaw, Fac Phys, Inst Expt Phys, Div Biophys, PL-02089 Warsaw, Poland..
    Darzynkiewicz, Edward
    Univ Warsaw, Fac Phys, Inst Expt Phys, Div Biophys, PL-02089 Warsaw, Poland.;Univ Warsaw, Ctr New Technol, PL-02097 Warsaw, Poland..
    Virtanen, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Molecular recognition of mRNA 5' cap by 3' poly(A)-specific ribonuclease (PARN) differs from interactions known for other cap-binding proteins2016In: Biochimica et Biophysica Acta - Proteins and Proteomics, ISSN 1570-9639, E-ISSN 1878-1454, Vol. 1864, no 4, p. 331-345Article in journal (Refereed)
    Abstract [en]

    The mRNA 5' cap structure plays a pivotal role in coordination of eukaryotic translation and mRNA degradation. Poly(A)-specific ribonuclease (PARN) is a dimeric exoribonuclease that efficiently degrades mRNA 3' poly(A) tails while also simultaneously interacting with the mRNA 5' cap. The cap binding amplifies the processivity of PARN action. We used surface plasmon resonance kinetic analysis, quantitative equilibrium fluorescence titrations and circular dichroism to study the cap binding properties of PARN. The molecular mechanism of 5' cap recognition by PARN has been demonstrated to differ from interactions seen for other known cap-binding proteins in that: i) the auxiliary biological function of 5' cap binding by the 3' degrading enzyme is accomplished by negative cooperativity of PARN dimer subunits; ii) non-coulombic interactions are major factors in the complex formation; and iii) PARN has versatile activity toward alternative forms of the cap. These characteristics contribute to stabilization of the PARN cap complex needed for the deadenylation processivity. Our studies provide a consistent biophysical basis for elucidation of the processive mechanism of PARN-mediated 3' mRNA deadenylation and provide a new framework to interpret the role of the 5' cap in mRNA degradation.

  • 9.
    Nosrati, Masoumeh
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology. Ferdowsi Univ Mashhad, Dept Chem, Mashhad, Iran.
    Solbak, Sara
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Nordesjö, Olle
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Nissbeck, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Dourado, Daniel F. A. R.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Andersson, Ken G
    Royal Institute of Technology, Stockholm, Sweden.
    Housaindokht, Mohammad Reza
    Ferdowsi University of Mashhad, Mashhad, Iran.
    Löfblom, John
    Royal Institute of Technology, Stockholm, Sweden.
    Virtanen, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Flores, Samuel Coulbourn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Insights from engineering the Affibody-Fc interaction with a computational-experimental method2017In: Protein Engineering Design & Selection, ISSN 1741-0126, E-ISSN 1741-0134, Vol. 30, no 9, p. 593-601Article in journal (Refereed)
    Abstract [en]

    The interaction between the Staphylococcal Protein A (SpA) domain B (the basis of the Affibody) molecule and the Fc of IgG is key to the use of Affibodies in affinity chromatography and in potential therapies against certain inflammatory diseases. Despite its importance and four-decade history, to our knowledge this interaction has never been affinity matured. We elucidate reasons why single-substitutions in the SpA which improve affinity to Fc may be very rare, and also discover substitutions which potentially serve several engineering purposes. We used a variation of FoldX to predict changes in protein-protein-binding affinity, and produce a list of 41 single-amino acid substitutions on the SpA molecule, of which four are near wild type (wt) and five are at most a factor of four from wt affinity. The nine substitutions include one which removes lysine, and several others which change charge. Subtle modulations in affinity may be useful for modifying column elution conditions. The method is applicable to other protein-protein systems, providing molecular insights with lower workload than existing experimental techniques.

  • 10. Perricaudet, M
    et al.
    Virtanen, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Akusjärvi, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pettersson, U
    Analysis of cloned mRNA sequences from the transforming region of adenovirus 21980In: Cold Spring Harbor Symposia on Quantitative Biology, ISSN 0091-7451, E-ISSN 1943-4456, Vol. 44, no 1, p. 471-476Article in journal (Refereed)
  • 11. Perricaudet, Michel
    et al.
    Akusjärvi, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Microbiology.
    Virtanen, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Microbiology.
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Microbiology.
    Structure of two spliced mRNAs from the transforming region of human subgroup C adenoviruses1979In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 281, no 5733, p. 694-696Article in journal (Other academic)
    Abstract [en]

    The papova viruses and the human adenoviruses are widely used as a model system to study cell transformation in vitro. In subgroup C human adenoviruses, fragment HpaI-E, which comprises as little as 4.5% of the adenovirus type 5 (ad5) DNA, is sufficient for transformation of rat embryo cells1. Analysis of messenger RNAs (mRNAs) from the transforming region of adenoviruses type 2 (ad2) has identified several spliced mRN A species2−4. Promoter mapping studies indicate that the leftmost early region contains two separate transcription units, E1A and E1B (ref. 5) (Fig. 1a). Region E1A is approximately equivalent HpaI-E. The complete nucleotide sequence of the HpaI-E fragment of ad5 was recently reported6. However, the spliced nature of early adenovirus mRNAs prevents a prediction of the amino acid sequence of the corresponding polypeptides directly from the DNA sequence. To study the structure of early ad2 mRNAs at the nucleotide level, we have used molecular cloning procedures to amplify the appropriate mRNA sequences. In this report, clones corresponding to the 12S and 13S mRNA from region E1A (Fig. 1c) have been isolated and characterised by hybridisation and sequence analysis. Our results enable us to predict the primary sequence of two related polypeptides from region E1A of human subgroup C adenoviruses.

  • 12.
    Ren, Yan-Guo
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Henriksson, Niklas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Virtanen, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Identification of Divalent Metal Ion Binding Sites in RNA/DNA-Metabolizing Enzymes by Fe(II)-Mediated Hydroxyl Radical Cleavage2014In: Handbook of RNA Biochemistry: Second, Completely Revised and Enlarged Edition / [ed] Roland K. Hartmann, Albrecht Bindereif, Astrid Schön and Eric Westhof, Wiley-Blackwell, 2014, 2, Vol. 1-2, p. 397-406Chapter in book (Refereed)
  • 13.
    Ren, Yan-Guo
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Martínez, Javier
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Kirsebom, Leif
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Virtanen, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Inhibition of Klenow DNA polymerase and poly(A)-specific ribonuclease by aminoglycosides2002In: RNA: A publication of the RNA Society, ISSN 1355-8382, E-ISSN 1469-9001, Vol. 8, no 11, p. 1393-1400Article in journal (Refereed)
    Abstract [en]

    Aminoglycosides are known to bind and perturb the function of catalytic RNA. Here we show that they also are potent inhibitors of protein-based catalysis using Escherichia coli Klenow polymerase (pol) and mammalian poly(A)-specific ribonuclease (PARN) as model enzymes. The inhibition was pH dependent and released in a competitive manner by Mg2+. Kinetic analysis showed that neomycin B behaved as a mixed noncompetitive inhibitor. Iron-mediated hydroxyl radical cleavage was used to show that neomycin B interfered with metal-ion binding in the active sites of both enzymes. Our analysis suggests a mechanism of inhibition where the aminoglycoside binds in the active site of the enzyme and thereby displaces catalytically important divalent metal ions. The potential causes of aminoglycoside toxicity and the usage of aminoglycosides to probe, characterize, and perturb metalloenzymes are discussed.

  • 14.
    Thuresson, Ann-Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Aström, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Aström, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Grönvik, Kjell Olov
    The National Veterinary Institute, Section of Immunology and Cell Culture, Biomedical Center, Uppsala.
    Virtanen, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    Multiple forms of poly(A) polymerases in human cells1994In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 91, no 3, p. 979-983Article in journal (Refereed)
    Abstract [en]

    We have cloned human poly(A) polymerase (PAP) mRNA as cDNA in Escherichia coli. The primary structure of the mRNA was determined and compared to the bovine PAP mRNA sequence. The two sequences were 97% identical at the nucleotide level, which translated into 99% similarity at the amino acid level. Polypeptides representing recombinant PAP were expressed in E. coli, purified, and used as antigens to generate monoclonal antibodies. Western blot analysis using these monoclonal antibodies as probes revealed three PAPs, having estimated molecular masses of 90, 100, and 106 kDa in HeLa cell extracts. Fractionation of HeLa cells showed that the 90-kDa polypeptide was nuclear while the 100- and 106-kDa species were present in both nuclear and cytoplasmic fractions. The 106-kDa PAP was most likely a phosphorylated derivative of the 100-kDa species. PAP activity was recovered in vitro by using purified recombinant human PAP. Subsequent mutational analysis revealed that both the N- and C-terminal regions of PAP were important for activity and suggested that cleavage and polyadenylylation specificity factor (CPSF) interacted with the C-terminal region of PAP. Interestingly, tentative phosphorylation sites have been identified in this region, suggesting that phosphorylation/dephosphorylation may regulate the interaction between the two polyadenylylation factors PAP and CPSF.

  • 15.
    Thuresson, Ann-Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Kirsebom, Leif A.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Virtanen, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Inhibition of poly(A) polymerase by aminoglycosides2007In: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 89, no 10, p. 1221-1227Article in journal (Refereed)
    Abstract [en]

    Aminoglycosides are potent inhibitors of bacterial growth and are used clinically as antibiotics. However, their usage has declined in recent years due to the emergence of resistance and severe toxic side effects. Here we show that human poly(A) polymerase gamma (PAPgamma) is inhibited by aminoglycosides. The inhibition was pH dependent and could be released by Mg(II) ions in a competitive manner suggesting that electrostatic interactions are important for inhibition and that the binding sites for aminoglycosides overlap with Mg(II) ion binding sites. Kinetic analysis revealed that aminoglycosides of the neomycin and kanamycin families behaved as mixed non-competitive inhibitors for the PAPgamma substrates oligoA15 and ATP. Interestingly, sisomicin and 5-epi-sisomycin showed a competitive mechanism of inhibition for the oligoA15 whereas they inhibited the ATP substrate mixed non-competitive. This implies that different aminoglycosides bind in different ways to a common binding pocket and suggests that the binding sites for related aminoglycosides are not overlapping even if they may share molecular determinants. Our study emphasizes the possibility that aminoglycoside toxicity could be due to interference with housekeeping enzymes involved in breaking and forming phosphodiester bonds.

  • 16.
    Virtanen, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Molecular analysis of adenovirus transformation1980Conference proceedings (editor) (Refereed)
  • 17.
    Virtanen, Anders
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Microbiology.
    Aleström, Peter
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Microbiology.
    Persson, Håkan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Microbiology.
    Katze, Michael G
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Microbiology.
    Petterson, Ulf
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Microbiology.
    An adenovirus agnogene1983In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 10, p. 2539-2548Article in journal (Refereed)
  • 18.
    Virtanen, Anders
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Henriksson, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Nilsson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Lindell, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Mechanism of processive and cap-stimulated mRNA poly(A) tail degradation2012In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26, p. 950.3-Article in journal (Other academic)
  • 19.
    Virtanen, Anders
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Henriksson, Niklas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Nilsson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Nissbeck, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Poly(A)-specific ribonuclease (PARN): An allosterically regulated, processive and mRNA cap-interacting deadenylase2013In: Critical reviews in biochemistry and molecular biology, ISSN 1040-9238, E-ISSN 1549-7798, Vol. 48, no 2, p. 192-209Article, review/survey (Refereed)
    Abstract [en]

    Deadenylation of eukaryotic mRNA is a mechanism critical for mRNA function by influencing mRNA turnover and efficiency of protein synthesis. Here, we review poly(A)-specific ribonuclease (PARN), which is one of the biochemically best characterized deadenylases. PARN is unique among the currently known eukaryotic poly(A) degrading nucleases, being the only deadenylase that has the capacity to directly interact during poly(A) hydrolysis with both the m 7 G-cap structure and the poly(A) tail of the mRNA. In short, PARN is a divalent metal-ion dependent poly(A)-specific, processive and cap-interacting 3'-5' exoribonuclease that efficiently degrades poly(A) tails of eukaryotic mRNAs. We discuss in detail the mechanisms of its substrate recognition, catalysis, allostery and processive mode of action. On the basis of biochemical and structural evidence, we present and discuss a working model for PARN action. Models of regulation of PARN activity by trans-acting factors are discussed as well as the physiological relevance of PARN.

  • 20.
    Virtanen, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine.
    Pettersson, U
    The molecular structure of the 9S mRNA from early region 1A of adenovirus 21983In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 165, no 3, p. 496-499Article in journal (Refereed)
  • 21.
    Virtanen, Anders
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Pettersson, U.
    Le Moullec, J.M.
    Tiollais, P.
    Perricaudet, M.
    Different mRNAs from the transforming region (EIB) of highly- and non-oncogenic human adenoviruses1982In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 295, no 5851, p. 705-707Article in journal (Refereed)
  • 22.
    Åström, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    Åström, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    Virtanen, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    A simple procedure for isolation of eukaryotic mRNA polyadenylation factors1991In: European Journal of Biochemistry, ISSN 0014-2956, E-ISSN 1432-1033, Vol. 202, no 3, p. 765-773Article in journal (Refereed)
    Abstract [en]

    We have devised a simple chromatographic procedure which isolates five polyadenylation factors that are required for polyadenylation of eukaryotic mRNA. The factors were separated from each other by fractionation of HeLa cell nuclear extract in two consecutive chromatographic steps. RNA cleavage at the L3 polyadenylation site of human adenovirus 2 required at least four factors. Addition of adenosine residues required only two of these factors. The fractionation procedure separates two components that are both likely to be poly(A) polymerases. The candidate poly(A) polymerases were interchangeable and participated during both RNA cleavage and adenosine addition. They were discriminated from each other by chromatographic properties, heat sensitivity and divalent cation requirement. We have compared our data with published information and have been able to correlate the activities that we have isolated to previously identified polyadenylation factors. However, we have not been able to assign one of the candidate poly(A) polymerases to a previously identified poly(A) polymerase. This simple fractionation procedure can be used for generating an in vitro reconstituted system for polyadenylation within a short period of time.

  • 23.
    Åström, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    Åström, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    Virtanen, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    In vitro deadenylation of mammalian mRNA by a HeLa cell 3' exonuclease1991In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 10, no 10, p. 3067-3071Article in journal (Refereed)
    Abstract [en]

    We have identified a 3' exonuclease in HeLa cell extracts which deadenylates mammalian mRNA and leaves the mRNA body intact after poly(A) removal. Only homopolymeric adenosine tails located at the 3' end were efficiently removed by the exonuclease. The poly(A) removing activity did not require any specific sequences in the mRNA body either for poly(A) removal or for accumulation of the deadenylated mRNA. We conclude that the poly(A) removing activity is a 3' exonuclease since (i) reaction intermediates gradually lose the poly(A) tail, (ii) degradation is prevented by the presence of a cordycepin residue at the 3' end and (iii) RNAs having internally located poly(A) stretches are poor substrates for degradation. The possible involvement of the poly(A) removing enzyme in regulating mRNA translation and stability is discussed.

1 - 23 of 23
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