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Modeling of the U1 snRNP assembly pathway in alternative splicing in human cells using Petri nets

ABSTRACT: The investigation of spliceosomal processes is currently a topic of intense research in molecular biology. In the molecular mechanism of alternative splicing, a multi-protein–RNA complex – the spliceosome – plays a crucial role. To understand the biological processes of alternative splicing, it is essential to comprehend the biogenesis of the spliceosome. In this paper, we propose the first abstract model of the regulatory assembly pathway of the human spliceosomal subunit U1. Using Petri nets, we describe its highly ordered assembly that takes place in a stepwise manner.

SUBMITTER: Maria Papageorgopoulou

PROVIDER: MODEL2410300001 | BioModels | 2024-10-31

REPOSITORIES: BioModels

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	MODEL2410300001?filename=Kielbassa2008%20Modeling%20of%20the%20U1%20snRNP%20assembly%20pathway%20in%20alternative%20splicing%20in%20human%20cells%20using%20Petri%20nets%20_%20Petr%20Nets%20layout.xml	Xml
	MODEL2410300001?filename=Kielbassa2008%20Modeling%20of%20the%20U1%20snRNP%20assembly%20pathway%20in%20alternative%20splicing%20in%20human%20cells%20using%20Petri%20nets_%20Petr%20Nets.xml	Xml

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Modeling of the U1 snRNP assembly pathway in alternative splicing in human cells using Petri nets.

Kielbassa J J Bortfeldt R R Schuster S S Koch I I

Computational biology and chemistry 20080725 1

The investigation of spliceosomal processes is currently a topic of intense research in molecular biology. In the molecular mechanism of alternative splicing, a multi-protein-RNA complex - the spliceosome - plays a crucial role. To understand the biological processes of alternative splicing, it is essential to comprehend the biogenesis of the spliceosome. In this paper, we propose the first abstract model of the regulatory assembly pathway of the human spliceosomal subunit U1. Using Petri nets, ...[more]

PMID: 18775676

Publication: 1/2

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Project description:Folding of newly synthesized proteins to the native state is a major challenge within the crowded cellular environment, since non-productive interactions can lead to misfolding, aggregation and degradation1. Cells cope with this challenge by coupling synthesis with polypeptide folding and by employing molecular chaperones to safeguard folding already cotranslationally2. However, little is known about the final step of folding, the assembly of polypeptides into complexes, although most of the cellular proteome forms oligomeric assemblies3. In prokaryotes, a proof-of-concept study showed that assembly of heterodimeric luciferase is an organized cotranslational process, facilitated by spatially confined translation of the subunits encoded on a polycistronic mRNA4. In eukaryotes, however, fundamental differences such as rarity of polycistronic mRNAs and different chaperone constellations raise the question whether assembly is also coordinated with translation. Here we provide a systematic and mechanistic analysis of protein complex assembly in eukaryotes using ribosome profiling. We determined the in vivo nascent subunits interactions of 12 hetero-oligomeric protein complexes of Saccharomyces cerevisiae at near-residue resolution. We find 9 complexes assemble cotranslationally; the 3 complexes that do not show cotranslational interactions are regulated by dedicated assembly chaperones5-7. Cotranslational assembly often occurs uni-directionally, with one fully synthesized subunit engaging its nascent partner subunit(s), thereby counteracting its aggregation propensity. The onset of cotranslational subunit association coincides sharply with full exposure of the nascent interaction domain at the ribosomal tunnel exit. The action of the ribosome-associated Hsp70 chaperone Ssb8 is coordinated with assembly. Ssb transiently engages partially synthesized interaction domains, then dissociates before the onset of partner subunit association, presumably to prevent premature assembly interactions. Our study shows that cotranslational subunit association is a prevalent mechanism for hetero-oligomers assembly in yeast and indicates that translation, folding and assembly of protein complexes are integrated processes in eukaryotes.