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Bücher Englische Bücher Wissen & Bildung Naturwissenschaft, Medizin, Informatik, Technik Biologie Mikrobiologie Investigations on structural and functional requirements of the formation of human pre-catalytic spliceosomes
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Investigations on structural and functional requirements of the formation of human pre-catalytic spliceosomes
Marc Schneider (Unbekannter Einband, Englisch)
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Pre-mRNA splicing is an essential process during gene expression. It is catalyzed by a highly dynamic machinery, the spliceosome. The spliceosome consists of five small nuclear ribonucleoprotein particles (snRNPs), namely U1, U2, U5 and U4/U6 snRNP, which are characterized by one or two uridine rich small nuclear RNAs (UsnRNA) and several associated proteins. The spliceosome assembles in a step… wise manner to splice out intervening sequences (introns) from the coding sequence (exons), which form the mature mRNA. The 5′ and 3′ end of the intron are recognized by U1 and U2 snRNP, which thereby form the spliceosomal complex A. Upon stable integration of the U4/U6.U5 tri-snRNP the pre-catalytic complex B is formed. In order to form an active centre the B complex needs to undergo dramatic conformational rearrangements, which include the replacement of the U1/5′SS interaction with a U6/5’SS, and disruption of the extensive U4/U6 base pairing. U6 snRNA subsequently engages in new intra- and intermolecular interactions, which are essential for the catalytic activity of the spliceosome. U1 and U4 snRNA leave the spliceosome and the activated complex B* is formed, which can perform the first catalytic step of splicing. The subsequently formed C complex performs the second transesterification reaction which ligates the adjacent exons and leads to the formation of the mature mRNA. The conformational rearrangements upon activation of the spliceosome are controlled by the RNA helicase hPrp28, Brr2 and the GTPase Snu114, which act as so-called molecular switches. hPrp28 is involved in the replacement of U1 by U6 snRNA at the 5′SS, whereas Brr2, whose activity is controlled by Snu114, disrupts the base pairing between U4 and U6 snRNA. As all three proteins are stable components of the U4/U6.U5 tri-snRNP, their activity needs to be tightly controlled to avoid premature activation of the spliceosome. Interestingly, recent experiments show that phosphorylation plays an important role for the interaction of hPrp28 with the U4/U6.U5 tri-snRNP and hence its activity during splicing. It is therefore conceivable that additional phosphorylation events control spliceosome assembly and activation.
My analysis of purified U4/U6.U5 tri-snRNP and B complex revealed that hPrp6 and hPrp31 are phosphorylated upon B complex formation. Phosphorylation sites could be detected via mass spectrometry (MS) and multiple alignment of hPrp6 and hPrp31 with homologues from other species demonstrated a high degree of conservation of those sites from human to Schizosaccharomyces pombe (S. pombe), suggesting that the sites might play an important role during splicing. Immunodepletion of hPrp4 kinase (hPrp4K) and rescue with recombinant hPrp4K showed that the phosphorylation of hPrp6 and hPrp31 was dependent on the presence of hPrp4K. Furthermore, depletion of hPrp4K stalled spliceosomes at the stage of B complex formation, without affecting U4/U6.U5 tri-snRNP integrity, which could still loosely bind to the pre-mRNA. Thus, hPrp4K is required for the stable integration of the tri-snRNP during B complex formation. These data are also consistent with the idea that hPrp6 and hPrp31 phosphorylation by hPrp4K contributes to the functional association of the tri-snRNP with the pre-mRNA during spliceosome assembly. In addition, they provide new insights into the molecular mechanism whereby Prp4K acts during splicing in humans. They further indicate that numerous phosphorylation events may contribute to spliceosome assembly as regulatory checkpoints in the human system.
Although, most investigations in recent years concentrated on cross-intron defined spliceosome assembly, the situation in the human system is more complicated. As introns are very long in humans and exons usually do not exceed a length of 300 nt, it is thought that U1 snRNP bound to the 5′SS and U2 snRNP bound to the upstream 3′SS interact across the exon to stabilize each other, a process termed exon definition. Subsequently, a swap from cross-exon to cross-intron definition must take place, in order to pair the 5′SS and 3′SS of an intron, to allow its excision. At present it remains unclear how this transition takes place and when a stable B complex is formed after exon definition. In order to address this question, I first characterized the factors involved in exon definition. My results suggest that stable binding of U2 snRNP is the decisive step during exon definition. Native MS2 affinity purification of cross-exon complexes revealed that the U4/U6.U5 trisnRNP is loosely associated via U2 snRNP with the exon RNA and that U1 snRNP is dispensable for U4/U6.U5 tri-snRNP recruitment. The addition of a 5′SS containing RNA oligonucleotide (oligo) in trans can be used to mimic the swap from cross-exon to cross-intron definition. Upon addition of such an oligo to crossexon complexes, a stable B-like complex forms, which differs from the exon complex in its sedimentation behaviour, protein composition, network of RNA-RNA interactions and posttranslational modifications. In summary, our data indicate that stable binding of U2 snRNP during exon definition leads to the recruitment of U4/U6.U5 tri-snRNP, which can be stabilized by the addition of a 5′SS containing RNA oligo. The reason for this stabilization is not entirely clear, but could involve both conformational and compositional changes. As the U4/U6.U5 tri-snRNP is already associated during exon definition, our data further suggest that cross-exon and cross-intron interactions might not be mutually exclusive. Dieses Produkt haben wir gerade leider nicht auf Lager.
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Technische Daten
Erscheinungsdatum
01.12.2009
Sprache
Englisch
EAN
9783866647091
Herausgeber
Mensch & Buch
Sonderedition
Nein
Autor
Marc Schneider
Seitenanzahl
140
Einbandart
Unbekannter Einband
-.-
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