title: Distinct domains of the spinal muscular atrophy protein SMN are required for targeting to Cajal bodies in mammalian cells.
abstract: Mutations of the survival motor neuron gene SMN1 cause the inherited disease spinal muscular atrophy (SMA). The ubiquitous SMN protein facilitates the biogenesis of spliceosomal small nuclear ribonucleoproteins (snRNPs). The protein is detected in the cytoplasm, nucleoplasm and enriched with snRNPs in nuclear Cajal bodies. It is structurally divided into at least an amino-terminal region rich in basic amino acid residues, a central Tudor domain, a self-association tyrosine-glycine-box and an exon7-encoded C-terminus. To examine the domains required for the intranuclear localization of SMN, we have used fluorescently tagged protein mutants transiently overexpressed in mammalian cells. The basic amino acid residues direct nucleolar localization of SMN mutants. The Tudor domain promotes localization of proteins in the nucleus and it cooperates with the basic amino acid residues and the tyrosine-glycine-box for protein localization in Cajal bodies. Moreover, the most frequent disease-linked mutant SMNDeltaex7 reduces accumulation of snRNPs in Cajal bodies, suggesting that the C-terminus of SMN participates in targeting to Cajal bodies. A reduced number of Cajal bodies in patient fibroblasts associates with the absence of snRNPs in Cajal bodies, revealing that intranuclear snRNA organization is modified in disease. These results indicate that direct and indirect mechanisms regulate localization of SMN in Cajal bodies.
authors.affiliation: Laboratoire de Biologie Cellulaire des Membranes, Institut Jacques Monod (IJM), UMR 7592 CNRS/Universités Paris 6 et 7, 2 Place Jussieu, 75251 Paris Cedex 05, France.
authors.forename: Benoît
authors.initials: B
authors.lastname: Renvoisé
authors.forename: Kevinee
authors.initials: K
authors.lastname: Khoobarry
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Gendron
authors.forename: Christian
authors.initials: C
authors.lastname: Cibert
authors.forename: Louis
authors.initials: L
authors.lastname: Viollet
authors.forename: Suzie
authors.initials: S
authors.lastname: Lefebvre
mesh_terms: D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D002522:Chlorocebus aethiops; D020541:Coiled Bodies / Q000737:chemistry / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D009134:Muscular Atrophy, Spinal / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D016601:RNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017411:Ribonucleoproteins, Small Nuclear / Q000378:metabolism; D055532:SMN Complex Proteins; D013329:Structure-Activity Relationship; D055533:Survival of Motor Neuron 1 Protein
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D017411:Ribonucleoproteins, Small Nuclear; D055532:SMN Complex Proteins; C526471:SMN1 protein, human; D055533:Survival of Motor Neuron 1 Protein