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PubMed1983

Polypeptide components of human small nuclear ribonucleoproteins.

Small nuclear RNA molecules (snRNAs) are associated with polypeptides in vivo, forming small nuclear ribonucleoprotein complexes (snRNPs). These snRNP complexes are targets for certain autoimmune antisera. Antisera of the type anti-Sm precipitate (and therefore define) a class including U1, U2, U4, U5, and U6 snRNAs, whereas antisera of the anti-RNP type precipitate only U1 snRNPs. We used these two types of autoimmune antisera (from patients with systemic lupus erythematosus) to study the polypeptide components in human cells. Sequential immunoprecipitation of the complexes from nuclear extracts with anti-RNP and anti-Sm antibodies, along with radioimmunoassay of protein transfers, identified four polypeptides of 14,000 (P14), 17,000 (P17), 26,000 (P26), and 27,000 (P27) daltons that are present on all members of this class, whereas a 68,000-dalton (P68) polypeptide is present only on U1 snRNPs. Based on the radioimmunoassay, three of these polypeptides, P17, P26, and P27, are also the antigens for anti-Sm antisera, whereas P68 is the antigen for anti-RNP antisera. Long-term phosphate labeling experiments show that the only detectably phosphorylated polypeptide is P68, which contains phosphoserine.

Amino Acids↗

PubMed2003

Small structural costs for evolution from RNA to RNP-based catalysis.

Typical RNA-based cellular catalysts achieve their active structures only as complexes with protein cofactors, implying that protein binding compensates for some structural deficiencies in the RNA. An unresolved question was the extent to which protein-facilitation imposes additional structural costs, by requiring that an RNA maintain structures required for protein binding, beyond those required for catalysis. We used nucleotide analog interference to identify initially 71 functional group substitutions at phosphate, 2'-ribose, and adenosine base positions that compromise RNA self-splicing in the bI5 group I intron. Protein-facilitated splicing by CBP2 suppresses 11 of 30 interfering substitutions at the RNA backbone and a greater fraction, 27 of 41, at the adenosine base, including at structures conserved among group I introns. Only one substitution directly interferes with protein binding but not with self-splicing. This substitution, plus three adenosine base modifications that interfere more strongly in CBP2-dependent splicing than in self-splicing, yield a cost for protein facilitation of only four functional groups, as approximated by this set of analogs. The small observed structural cost provides a strong physical rationale for the evolutionary drive from RNA to RNP-based function in biology. Remarkably, the four extra requirements do not appear to report disruption of direct protein-RNA contacts and instead likely reflect design against misfolding rather than for maintenance of a protein-binding site.

Animals↗

PubMed1999

Should we kill the messenger? The role of the surveillance complex in translation termination and mRNA turnover.

Eukaryotes have evolved conserved mechanisms to rid cells of faulty gene products that can interfere with cell function. mRNA surveillance is an example of a pathway that monitors the translation termination process and promotes degradation of transcripts harboring premature translation termination codons. Studies on the mechanism of mRNA surveillance in yeast and humans suggest a common mechanism where a "surveillance complex" monitors the translation process and determines whether translation termination has occurred at the correct position within the mRNA. A model will be presented that suggests that the surveillance complex assesses translation termination by monitoring the transition of an RNP as it is converted from a nuclear to a cytoplasmic form during the initial rounds of translation.

Animals↗

PubMed2001

Hierarchical assembly of the Alu domain of the mammalian signal recognition particle.

The mammalian signal recognition particle (SRP) catalytically promotes cotranslational translocation of signal sequence containing proteins across the endoplasmic reticulum membrane. While the S-domain of SRP binds the N-terminal signal sequence on the nascent polypeptide, the Alu domain of SRP temporarily interferes with the ribosomal elongation cycle until the translocation pore in the membrane is correctly engaged. Here we present biochemical and biophysical evidence for a hierarchical assembly pathway of the SRP Alu domain. The proteins SRP9 and SRP14 first heterodimerize and then initially bind to the Alu RNA 5' domain. This creates the binding site for the Alu RNA 3' domain. Alu RNA then undergoes a large conformational change with the flexibly linked 3' domain folding back by 180 degrees onto the 5' domain complex to form the final compact Alu ribonucleoprotein particle (Alu RNP). We discuss the possible mechanistic consequences of the likely reversibility of this final step with reference to translational regulation by the SRP Alu domain and with reference to the structurally similar Alu RNP retroposition intermediates derived from Alu elements in genomic DNA.

Alu Elements↗

PubMed1961

Electron microscopy of the oxyntic cell in the gastric glands of the bullfrog (Rana catesbiana). I. The non-acid-secreting gastric mucosa.

The fine structure of the oxyntic cell from the gastric glands of the bullfrog was studied in lead hydroxide-stained sections of gastric mucosa fixed in buffered osmium tetroxide and embedded in n-butyl methacrylate. The oxyntic cell in non-acid-secreting stomachs (gastric juice pH, 7.4-7.8) is characterized by: (a) numerous closely packed smooth surfaced vesicular and tubular profiles disposed randomly in the cell; some of these elements show interconnections making it possible to identify this component with smooth surfaced endoplasmic reticula of certain other cell types, (b) a small percentage of rough surfaced profiles characteristic of endoplasmic reticula possessing RNP particles on the outer membrane surfaces, (c) a Golgi complex consisting of multiple isolated non-polarized arrays of smooth surfaced parallel elongated profiles and associated vesicular elements, (d) a sparse granular component (140 A) scattered freely in the cytoplasmic matrix, (e) numerous mitochondria with a dense matrix and containing an unusually large number of closely approximated cristae, (f) a number of zymogen granules consisting of either a dense body limited by a membrane or surrounded by a halo of less dense material which is in turn limited by a membrane, and (g) a number of granules ( approximately 260 A) containing several smaller granules ( approximately 80 A) identified presumably as glycogen. Intracellular canaliculi were not observed. Instead the free surface of the oxyntic cell facing the lumen of the gastric gland shows a complicated plication of the plasma membrane. Intercellular canaliculi are seen frequently between adjacent oxyntic cells. The walls of these canaliculi are made up of folded and ruffled cell membranes. The basal surface of the cell also exhibited this type of configuration. Occasional smooth surfaced profiles are seen communicating with the free surface, the wall of an intercellular canaliculus, or the basal surface of the cell. Although nerve endings were not found in association with oxyntic cells, unmyelinated nerves were observed in the vicinity of the gastric glands.

Animals↗

PubMed1984

Distribution and utilization of 5 S-RNA-binding proteins during the development of Xenopus oocytes.

At early stages of oogenesis in Xenopus laevis most of the ribosomal 5S RNA is complexed with three proteins to form two types of cytoplasmic RNP storage particle. A particle sedimenting at 42S contains 5S RNA and tRNA together with two proteins of Mr 48000 (P48) and Mr 43000 (P43) and a second particle sedimenting at 7S contains 5S RNA plus a protein of Mr 40000 (P40, also known as the transcription factor, TFIIIA). In this report we use antibodies monospecific for each protein to follow the movement of 5S RNA from nucleus to cytoplasm to nucleolus to cytoplasm and to determine the fate of each of the proteins that associate with 5S RNA during these transitions. Both P48 and P43 have roles additional to the formation of the 42S RNP storage particle; P48 is detected in the nucleus during early oogenesis and is cleaved to yield an Mr-33000 fragment that remains associated with 5S RNA that is excess to ribosome requirement during late oogenesis; P43 appears to be cleaved to yield fragments of Mr 28000 and 17000, the latter being present in ribosomal fractions. Apparently, there is no function for P40 in addition to those already described in transcription of 5S RNA genes and in storage of 5S RNA as a 7S RNP particle.

Animals↗

PubMed1992

Three novel functional variants of human U5 small nuclear RNA.

We have identified and characterized three new variants of U5 small nuclear RNA (snRNA) from HeLa cells, called U5D, U5E, and U5F. Each variant has a 2,2,7-trimethylguanosine cap and is packaged into an Sm-precipitable small nuclear ribonucleoprotein (snRNP) particle. All retain the evolutionarily invariant 9-base loop at the top of stem 1; however, numerous base changes relative to the abundant forms of U5 snRNA are present in other regions of the RNAs, including a loop that is part of the yeast U5 minimal domain required for viability and has been shown to bind a protein in HeLa extracts. U5E and U5F each constitute 7% of the total U5 population in HeLa cells and are slightly longer than the previously characterized human U5 (A, B, and C) species. U5D, which composes 5% of HeLa cell U5 snRNAs, is present in two forms: a full-length species, U5DL, and a shorter species, U5DS, which is truncated by 15 nucleotides at its 3' end and therefore resembles the short form of U5 (snR7S) in Saccharomyces cerevisiae. We have established conditions that allow specific detection of the individual U5 variants by either Northern blotting (RNA blotting) or primer extension; likewise, U5E and U5F can be specifically and completely degraded in splicing extracts by oligonucleotide-directed RNase H cleavage. All variant U5 snRNAs are assembled into functional particles, as indicated by their immunoprecipitability with anti-(U5) RNP antibodies, their incorporation into the U4/U5/U6 tri-snRNP complex, and their presence in affinity-purified spliceosomes. The higher abundance of these U5 variants in 293 cells compared with that in HeLa cells suggests possible roles in alternative splicing.

Base Sequence↗

PubMed1990

Pathogenesis of anti-Ro/SS-A autoantibody-associated cutaneous lupus erythematosus.

Patients with several clinically distinctive types of cutaneous LE (e.g., SCLE, neonatal LE) frequently are found to have autoantibodies to the Ro RNP particle present in their circulation. Some studies suggest that these antibodies might be capable of directly triggering the type of histopathologic changes seen in SCLE and neonatal LE through immunologic effector mechanisms such as ADCC. Other investigative results, however, are not compatible with this hypothesis. A better understanding of the molecular configuration of the Ro small cellular RNP particle, the factors that regulate the expression of this complex autoantigen system in epidermal keratinocytes, and the overall pathogenetic potential of the Ro autoimmune response should provide some insight into this seeming paradox.

Antibodies, Antinuclear↗

PubMed1984

Circulating immune complexes in systemic scleroderma.

Circulating immune complexes were detected by the immunoelectrophoretic method in 18 of 29 (62 per cent) of patients with systemic scleroderma. The presence of immune complexes did not correlate with that of antinuclear antibodies to dsDNA, DNP, RNP, and Sm. The mean levels of immunoglobulins G, A, and M as well as of C3 were significantly higher in patients with systemic scleroderma than in blood donors.

Antibodies, Anti-Idiotypic↗

PubMed1981

A ribonuclease-resistant cytoplasmic 10 S ribonucleoprotein of chick embryonic muscle. A potent inhibitor of cell-free protein synthesis.

A ribonucleoprotein (RNP) particle sedimenting at 10 S in sucrose gradients had been isolated from the post-polysomal fraction of homogenates of 14-day-old chick embryonic leg and breast muscle by sucrose gradient fractionation and gel filtration. The 10 S RNP contains a 4 S RNA species (base composition: AMP, .3%; GMP, 22.2%; CMP, 24.2%; and UMP, 23.2%), and shows three major bands in the 70-90-nucleotide size range by polyacrylamide gel electrophoresis in 99% formamide. The 4 S RNA does not contain oligo(U)- and oligo(A)-rich tracts. The RNP has a characteristic buoyant density of 1.410 g/ml, which corresponds to an RNA/protein ratio of about 1:4. The UV absorption spectra of the RNP is very distinct from that of its RNA component. Both 4 S RNA and the 10 S RNP are potent inhibitors of translation of a variety of mRNAs such as chick muscle poly(A)+ mRNA, rabbit globin mRNA, EMC virus RNA, and poly(A)- and mRNA of rat liver in micrococcal nuclease-treated rabbit reticulocyte lysate. The inhibitory action of the RNA and the RNP on mRNA translation appears to involve the initiation process. The RNA and RNP do not have a nuclease activity associated with them. The hyperchromicity profile of the inhibitory RNA with increasing temperature indicates that it does not contain a significant amount of double-stranded structure. This is also supported by the complete loss of biological activity of the RNA by treatment with pancreatic RNase. In contrast, the inhibitory activity of the RNP was resistant to RNase. Electrophoresis of the protein moieties of the inhibitory RNP using both one- and two-dimensional gel techniques in the presence of sodium dodecyl sulfate shows a complex pattern of polypeptides of Mr = 12,000-150,000. The protein pattern of the 10 S particle is quite different from those of free and polysomal mRNP and poly(A)-protein complexes of chick embryonic muscles, indicating that most, if not all of the mRNA-associated proteins, are absent in the 19 S RNP. The properties of the inhibitory RNA indicate that it is different from the various low molecular weight RNA species which are involved in the modulation of protein synthesis in cell-free systems. It is concluded that the 10 S particle represents a novel class of RNP, which may be involved in posttranscriptional regulation of protein synthesis in embryonic muscles.

Animals↗

PubMed1983

Ultrastructural localization of Ag-NOR proteins and nucleic acids in reticulated nucleoli.

Nucleoli with a thread-like fibrillar structure found in several human breast cancer cells were investigated for the localization of Ag-NOR proteins, RNA, DNA and associated nucleoproteins. Various cytochemical techniques were applied: the one-step silver method for Ag-NOR proteins, the Bernhard's staining preferential for RNP, the Feulgen-like osmium-ammine reaction for DNA and the RNase- and DNase-gold complexes for the demonstration of RNA and DNA respectively. Staining for Ag-NOR proteins was restricted to the edge of the threads or cords and to the nodes of the nucleolar network. The Bernhard's EDTA technique gave a positive staining of the entire nucleoli and on small peripheral granules which were linked to the nucleolar cords by fine RNP fibrils. Localization of RNA molecules by the RNase-gold complex showed a similar pattern, dense labeling by gold particles over the nucleoli and at the periphery of the cords. DNA molecules were revealed by the osmium-ammine technique in small nucleoplasmic clumps and at the edge of the nucleolar cords. Similar results were obtained by applying the DNase-gold complex which showed a labeling by gold particles over the dispersed chromatin and at the edge of the nucleolar cords. The consistency of the results obtained speaks in favor of their specificity and seems to demonstrate the simultaneous localization of certain Ag-NOR proteins, DNA and RNA molecules at the edge of the nucleolar cords. This edge of nucleolar cords becomes then the candidate for the site of nucleolar transcriptional activity.

Breast Neoplasms↗

PubMed1987

5S-rRNA-containing ribonucleoproteins from rabbit muscle and liver. Complex and partial primary structures.

A 5S-rRNA-containing ribonucleoprotein was purified to homogeneity from a rabbit muscle extract through its affinity to phosphofructokinase-1 and then structurally characterized. This RNP was compared to the 5S-rRNA-containing ribonucleoprotein extracted from rabbit liver ribosomal 60S subunits with EDTA. Analytical gel filtration revealed a molecular mass of 70-80 kDa for both complexes. Gel electrophoresis of the ribosomal complex revealed three protein components, one migrating as a band of 35 kDa and two other small polypeptides of apparently 16.5 kDa and 17.5 kDa. In the sarcoplasmic RNP these small polypeptides were absent. However, besides a major component of 35 kDa, up to five slightly larger and smaller species of 31.5-36.5 kDa were detected. Despite this heterogeneity, only one N-terminal amino acid sequence was obtained for the isolated sarcoplasmic protein, suggesting a C-terminal heterogeneity of one single polypeptide. Within the first 46 amino acid residues no difference between the sequences of the isolated 35-kDa components of sarcoplasmic and ribosomal complexes was found. Homology criteria indicated that this component belongs to the ribosomal protein L5 family. The RNA was identified by complete enzymatic sequencing as 5S rRNA; it was also identical in both complexes and is strongly homologous to 5S rRNA of man. Both L5-5S-RNA complexes could be resolved by hydroxyapatite chromatography into three species still consisting of both protein and RNA. 5'-Terminal dephosphorylation experiments showed that this heterogeneity is exclusively due to the differing number (1-3) of 5'-terminal phosphates. The two additional low-molecular-mass proteins were stably associated to the ribosomal RNP at high salt concentrations in a stoichiometry of about 2:1. They were identified as the acidic phosphoproteins P2/P3 by N-terminal sequencing. High phosphate concentrations facilitated their dissociation from the L5-5S-RNA complex. For the sarcoplasmic L5-5S-RNA complex a hitherto unknown interaction with phosphofructokinase-1, affecting the enzymatic properties, was demonstrated.

Amino Acid Sequence↗

PubMed1981

Ro small cytoplasmic ribonucleoproteins are a subclass of La ribonucleoproteins: further characterization of the Ro and La small ribonucleoproteins from uninfected mammalian cells.

Small ribonucleic acid (RNA)-protein complexes precipitated by anti-Ro and anti-La antibodies from lupus patients have been examined with emphasis on their RNA components. In both ribonucleoprotein (RNP) classes, the numbers of different RNA molecules and their sequences vary between mouse and human cells. The complex mixtures of La RNAs include two previously sequenced 4.5S RNAs from mouse cells and 5S ribosomal RNA-like molecules from both mouse and human cells. All Ro and La RNAs possess 5-triphosphates. Some La RNAs have internal modifications typical of transfer RNAs. The Ro RNPs are quite stable and are localized by immunofluorescence in the cell cytoplasm, whereas the majority of the La RNPs turn over rapidly and reside in the nucleus. Despite these differences, reconstitution experiments show that the Ro particles carry the La as well as the Ro determinant. Studies using a nuclear transcription system demonstrate that most of the La RNAs are synthesized by RNA polymerase III. The possibility that the La protein(s) functions in the transcription or maturation of all RNA polymerase III transcripts is discussed.

Animals↗

PubMed1984

Monoclonal antibody characterization of the C proteins of heterogeneous nuclear ribonucleoprotein complexes in vertebrate cells.

The C proteins (C1 and C2) are major constituents of the 40S subparticle of heterogeneous nuclear ribonucleoprotein complexes (hnRNPs) (Beyer, A.L., M.E. Christensen, B.W. Walker, and W.M. LeStourgeon, 1977, Cell, 11:127-138) and are two of the most prominent proteins that become cross-linked by ultraviolet light to heterogeneous nuclear RNA (hnRNA) in vivo. Studies are described here on the characterization of the C proteins in vertebrate cells using monoclonal and polyclonal antibodies. Monoclonal antibodies to genuine RNP proteins, including the C proteins, were obtained by immunizing mice with purified complexes of poly(A)+ hnRNA and poly(A)+ mRNA with their contacting proteins in vivo obtained by ultraviolet cross-linking the complexes in intact cells (Dreyfuss, G., Y.D. Choi, and S.A. Adam, 1984, Mol. Cell. Biol., 4:1104-1114). One of the monoclonal antibodies identified the C proteins in widely divergent species ranging from human to lizard. In all species examined, there were two C proteins in the molecular weight range of from 39,000 to 42,000 for C1, and from 40,000 to 45,000 for C2. The two C proteins were found to be highly related to each other; they were recognized by the same monoclonal antibodies and antibodies raised against purified C1 reacted also with C2. In avian, rodent, and human cells the C proteins were phosphorylated and were in contact with hnRNA in vivo. Immunofluorescence microscopy demonstrated that the C proteins are segregated to the nucleus. Within the nucleus the C proteins were not found in nucleoli and were not associated with chromatin as seen in cells in prophase. These findings demonstrate that C proteins with similar characteristics to those in humans are ubiquitous components of hnRNPs in vertebrates.

Animals↗

PubMed2004

Two-hybrid Mpp10p interaction-defective Imp4 proteins are not interaction defective in vivo but do confer specific pre-rRNA processing defects in Saccharomyces cerevisiae.

The SSU processome is a large, evolutionarily conserved ribonucleoprotein (RNP), consisting of the U3 snoRNA and at least 28 protein components, that is required for biogenesis of the 18S rRNA. We tested the function of one protein-protein interaction in the SSU processome, Mpp10p-Imp4p, in ribosome biogenesis. Exploiting the reverse two-hybrid system, we screened for mutated Imp4 proteins that were conditionally defective for interaction with Mpp10p. Three different imp4 sequences were isolated that: (i) conferred conditional growth in the two-hybrid strain; (ii) complemented the disrupted imp4; (iii) conferred conditional growth in the context of their normal cellular function; and (iv) resulted in defective pre-rRNA processing at the non-permissive temperatures. Domain swapping revealed that mutations that conferred cold sensitivity resided in the N-terminal coiled-coil domain while mutations in the C-terminus conferred temperature sensitivity. Surprisingly, the mutated Imp4 proteins were not measurably defective for interaction with Mpp10p in the context of the SSU processome. This suggests that other members of the complex may contribute to maintaining the Mpp10p-Imp4p interaction in this large RNP. Since protein-protein interactions are critical for many different aspects of cellular metabolism, our work has implications for the study of other large protein complexes.

Amino Acid Sequence↗

PubMed2006

Dynamic association and localization of human H/ACA RNP proteins.

Mammalian H/ACA RNPs are essential for ribosome biogenesis, pre-mRNA splicing, and telomere maintenance. To form mature RNA-protein complexes, one H/ACA RNA associates with four core proteins. In the cell, this process is assisted by at least one nuclear assembly factor, NAF1. Here we report several unanticipated dynamic aspects of H/ACA RNP proteins. First, when overexpressed, NAF1 delocalizes to the cytoplasm. However, its nucleocytoplasmic shuttling properties remain unaffected. These observations demonstrate a subtle equilibrium between NAF1 expression levels and the availability of NAF1 nuclear binding sites. Second, although NAF1 is excluded from mature RNPs in nucleoli and Cajal bodies, NAF1 associates with mature H/ACA RNA in cell lysates. This association occurs post-lysis because it is observed even when NAF1 and the H/ACA RNA are expressed in separate cells. This documents a protein-RNP association in cell lysates that is absent from intact cells. Third, in similar experiments, all H/ACA core proteins, except NAP57, exchange with their exogenous counterparts, portraying an unexpected dynamic picture of H/ACA RNPs. Finally, the irreversible association of only NAP57 with H/ACA RNA and the conundrum that only NAP57 is mutated in X-linked dyskeratosis congenita (even though most core proteins are required for maintaining H/ACA RNAs) may be more than a coincidence.

Active Transport, Cell Nucleus↗

PubMed1983

Isolation of intact Sm/RNP antigens from rabbit thymus.

A comparison of the immunologically reactive components of the highly conserved Sm and RNP autoantigens from various mammalian tissue sources suggested the complete absence of a major 26K to 27K Sm-specific polypeptide in rabbit thymus extracts prepared by conventional procedures. A simple modification of the solubilization protocol, achieved by sonicating a suspension of commercial rabbit thymus acetone powder in 0.35 M NaCI, gave an extract containing the full complement of immunologically reactive Sm and RNP proteins detectable in other mammalian species. Without further manipulation, extracts were immediately passed through an immunoaffinity column constructed from human SLE IgG with both anti-Sm and anti-RNP reactivities. The proteins of the purified Sm/RNP were recovered in sufficient quantities for direct analysis by protein staining or immunoblot assays. The antigenic polypeptides were recovered intact and consisted of a single 73K RNP-specific species together with Sm-specific proteins of 26K to 27K (a doublet) and 13K. These proteins were easily visible by protein stain as were nonantigenic components of 35K, 32K, 11K, and less than 10K. The same polypeptides were present in affinity-purified Sm/RNP from HeLa cells, although the RNP protein was slightly smaller. The resolution and integrity of the complexes isolated by this simple two-step procedure, requiring less than 4 hr for completion, is remarkable, and the protein composition of the product compares quite favorably with antigens isolated from other sources by considerably more lengthy and laborious procedures.

Animals↗

PubMed2001

Molecular mechanisms in spinal muscular atrophy: models and perspectives.

Spinal muscular atrophy is an autosomal-recessive disorder that is caused by homozygous mutations or deletion of the telomeric copy of the survival of motor neurone (SMN) gene on human chromosome 5q13. The SMN gene is present as an inverted repeat in this chromosomal region, and both SMN genes are expressed. They differ by the preferential expression of a full-length transcript from the telomeric copy and a truncated SMN protein from the centromeric SMN gene, which lacks the carboxyl-terminal portions of the protein encoded by exon 7. The SMN protein is part of multiprotein complexes in the cytoplasm and the nucleus that are involved in spliceosomal small-nuclear RNP assembly. This function depends on interaction with spliceosomal Sm core proteins. Recent data have also shown that the SMN protein interacts with RNA polymerase II, thus implying additional functions in messenger RNA transcription, possibly by assembly of RNA polymerase II transcription complexes. Thus, the SMN protein is involved in critical steps of messenger RNA transcription and processing, and current research efforts are directed at identifying the specificity of these defects for the pathophysiological changes in motor neurones that occur in spinal muscular atrophy.

Animals↗