NEW EMBO MEMBER'S REVIEW: Structure, function and evolution of the signal recognition particle

Nagai, Kiyoshi; Oubridge, Chris; Kuglstatter, A.; Elena, María; Isel, Catherine; Jovine, Luca

doi:10.1093/emboj/cdg337

Cited by 144 publications

(92 citation statements)

References 54 publications

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“…T he signal recognition particle (SRP) is a highly conserved ribonucleotide-protein complex involved in cotranslational membrane targeting of signal-peptide-bearing proteins (1). The SRP pathway is conserved in all domains of life and has been considered crucial for the vitality of all organisms (2)(3)(4)(5)(6).…”

mentioning

confidence: 99%

Streptococcal viability and diminished stress tolerance in mutants lacking the signal recognition particle pathway or YidC2

Hasona

Crowley

Lévesque

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

105

144

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The signal recognition particle (SRP)-translocation pathway is conserved in all three domains of life and delivers membrane and secretory proteins to the cytoplasmic membrane or endoplasmic reticulum. We determined the requirement in the cariogenic oral pathogen Streptocococcus mutans of the three universally conserved elements of the SRP pathway: Ffh͞SRP54, scRNA, and FtsY͞SR␣. Previously, we reported that insertional interruption of S. mutans ffh was not lethal, but resulted in acid sensitivity. To test whether S. mutans could survive extensive disruption of the SRP pathway, single and double deletions of genes encoding Ffh, scRNA, and FtsY were generated. Without environmental stressors, all mutant strains were viable, but unlike the wild-type, none could initiate growth at pH 5.0 or in 3.5% NaCl. Survival of challenge with 0.3 mM H2O2 was also diminished without ffh. Members of the YidC͞Oxa1͞Alb3 family are also ubiquitous, involved in the translocation and assembly of membrane proteins, and have been identified in prokaryotes͞mitochondria͞chloroplasts. Two genes encoding YidC homologs, YidC1 and YidC2, are present in streptococcal genomes with both expressed in S. mutans. Deletion of YidC1 demonstrated no obvious phenotype. Elimination of YidC2 resulted in a stress-sensitive phenotype similar to SRP pathway mutants. Mutants lacking both YidC2 and SRP components were severely impaired and barely able to grow, even in the absence of environmental stress. Here, we report the dispensability of the cotranslational SRP protein translocation system in a bacterium. In S. mutans, this pathway contributes to protection against rapid environmental challenge and may overlap functionally with YidC2.protein translocation ͉ streptococcus ͉ Ffh ͉ FtsY ͉ membrane biogenesis

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mentioning

confidence: 99%

Streptococcal viability and diminished stress tolerance in mutants lacking the signal recognition particle pathway or YidC2

Hasona

Crowley

Lévesque

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

105

144

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“…TER functional specialization could have been facilitated by the appropriation of RNA-binding proteins that served to stabilize favorable TER conformations. Telomerase may thus have gained a stepwise, hierarchical biogenesis strategy in its evolution from functional protein to cofunctional RNP, a strategy previously implicated in the evolution of ancestral RNAs to modern-day RNP machines such as the ribosome [33][34][35] . …”

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confidence: 99%

A telomerase holoenzyme protein enhances telomerase RNA assembly with telomerase reverse transcriptase

Prathapam

Witkin

O’Connor

et al. 2005

Nat Struct Mol Biol

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Telomerase maintains the simple sequence repeats at chromosome ends, protecting cells from genomic rearrangement, proliferative senescence and death. The telomerase reverse transcriptase (TERT) and telomerase RNA (TER) alone can assemble into active enzyme in a heterologous cell extract, but the physiological process of telomerase biogenesis is more complex. The endogenous accumulation of Tetrahymena thermophila TERT and TER requires an additional telomerase holoenzyme protein, p65. Here, we reconstitute this cellular pathway for telomerase ribonucleoprotein biogenesis in vitro. We demonstrate that tandem RNA interaction domains in p65 recognize the sequence of the TER 3′ stem. Notably, the p65-TER complex recruits TERT much more efficiently than does TER alone. Using bacterially expressed p65 and TERT polypeptides, we show that p65 enhances TERT-TER interaction by a mechanism involving a conserved bulge in the protein-bridging TER molecule. These findings reveal a pathway for telomerase holoenzyme biogenesis that preassembles TER for TERT recruitment.Cellular ribonucleoprotein (RNP) biogenesis has gained attention as a dynamic, regulated cascade of events that can be affected in human disease 1-3. RNPs assemble in vivo aided both by assembly chaperones, which contribute transient interactions, and by architectural RNA-binding proteins, which remain integral components of an assembled RNP 4 . Progress in the elucidation of physiological RNP biogenesis mechanisms has been impeded by the limited success in reconstitution of ordered protein and RNA assembly pathways in vitro.TERT and TER can assemble in rabbit reticulocyte lysate (RRL) to form a minimal recombinant telomerase RNP 5 . The physiological process of telomerase enzyme biogenesis, however, seems more complex. In vivo, human TER accumulation and telomere length maintenance are compromised by disease-associated single-residue substitutions in the RNA-binding protein dyskerin 6,7 . In budding yeast, TER accumulation requires RNAbinding proteins from the Sm family 8 . The potentially pleiotropic impact of vertebrate dyskerin or yeast Sm protein alterations complicates the interpretation of their direct roles in telomerase RNP assembly. Additionally, studies of these RNP assembly pathways in vitro are hampered by the inability to reconstitute a dyskerin or Sm RNP efficiently in the absence of other, typically concerted cellular events. In the biological context, it was thus unresolved whether TERT assembles with TER unassisted or only transiently chaperoned, or whether [9][10][11][12] . Genetic depletion of T. thermophila p65 reduces TER accumulation without impact on other small nuclear RNAs, suggesting that in contrast to vertebrate dyskerin or yeast Sm proteins, p65 has a telomerase-specific function in RNP biogenesis 9 . Based on these and additional findings, we proposed a p65-dependent pathway for the physiological biogenesis of T. thermophila telomerase RNP. Here, we test the proposed telomerase RNP assembly pathway by reconstituting the inter...

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“…in this study, using a third-generation lentivirus, we successfully constructed recombinant lentivirus vectors of the nT4-al fusion gene. in this delivery system, the alphastatin sequence alone is not sufficient for efficient translation and secretion in mammalian cells (21)(22)(23)(24); therefore, the human neurotrophin-4 signal peptide and pro-region sequence (nT4) were fused in-frame to the end of the coding sequence and a stop codon was appended to the end of the alphastatin coding sequence (Fig. 1a).…”

Section: A B Discussionmentioning

confidence: 99%

Construction of recombinant lentivirus vector for tumor vasoinhibitory peptide alphastatin gene delivery

Guo

2010

Mol Med Rep

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Abstract. angiogenesis is a prerequisite for tumor progression and metastasis. alphastatin, as an endogenous angiogenesis inhibitor, was recently used as an anticancer agent in several tumor models. We constructed recombinant self-inactivating lentivirus vectors expressing alphastatin and evaluated their ability to transfer genes into human umbilical vein endothelial cells (HuVecs) as well as their antiangiogenic activities in vitro. Recombinant self-inactivating lentiviral vectors efficiently and stably transduced endothelial cells, and lentivirus-transduced HuVecs were capable of sustainedly secreting the antiangiogenesis peptide alphastatin. long-term expression and secretion of alphastatin resulted in significant inhibition of endothelial cell angiogenesis induced by vascular endothelial growth factor. This report presents the first use of lentivirus-based vectors to deliver the endogenous angiogenesis inhibitor alphastatin, and suggests the potential utility of antiangiogenic gene therapy with lentiviral vectors for the treatment of cancer.

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NEW EMBO MEMBER'S REVIEW: Structure, function and evolution of the signal recognition particle

Cited by 144 publications

References 54 publications

Streptococcal viability and diminished stress tolerance in mutants lacking the signal recognition particle pathway or YidC2

Streptococcal viability and diminished stress tolerance in mutants lacking the signal recognition particle pathway or YidC2

A telomerase holoenzyme protein enhances telomerase RNA assembly with telomerase reverse transcriptase

Construction of recombinant lentivirus vector for tumor vasoinhibitory peptide alphastatin gene delivery

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