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Pseudoknots in prion protein mRNAs confirmed by comparative sequence analysis and pattern searching
I Barrette1, G Poisson, P Gendron
1Département d'Informatique et de Recherche Opérationnelle, Université de Montréal, CP 6128, Succ. Centre-Ville, Montréal, Québec H3C 3J7, Canada.
Abstract:
The human prion gene contains five copies of a 24 nt repeat that is highly conserved among species. An analysis of folding free energies of the human prion mRNA, in particular in the repeat region, suggested biased codon selection and the presence of RNA patterns. In particular, pseudoknots, similar to the one predicted by Wills in the human prion mRNA, were identified in the repeat region of all available prion mRNAs available in GenBank, but not those of birds and the red slider turtle. An alignment of these mRNAs, which share low sequence homology, shows several co-variations that maintain the pseudoknot pattern. The presence of pseudoknots in yeast Sup35p and Rnq1 suggests acquisition in the prokaryotic era. Computer generated three-dimensional structures of the human prion pseudoknot highlight protein and RNA interaction domains, which suggest a possible effect in prion protein translation. The role of pseudoknots in prion diseases is discussed as individuals with extra copies of the 24 nt repeat develop the familial form of Creutzfeldt-Jakob disease.
Insights
The human prion gene
Area of Science:
- Molecular Biology
- Genetics
- Bioinformatics
Background:
- The human prion gene features a conserved 24-nucleotide repeat.
- RNA structure analysis suggests specific patterns within the prion gene's mRNA.
- Previous research predicted pseudoknots in human prion mRNA.
Purpose of the Study:
- To investigate RNA patterns, specifically pseudoknots, in prion gene mRNAs across species.
- To explore the potential role of these RNA structures in prion protein translation and disease.
Main Methods:
- Analysis of folding free energies of human prion mRNA.
- Identification and alignment of prion mRNA sequences from GenBank.
- Computer-generated three-dimensional structure modeling of prion pseudoknots.
Main Results:
- Pseudoknots were identified in prion mRNAs of various species, excluding birds and turtles.
- Co-variation analysis revealed conserved pseudoknot patterns despite low sequence homology.
- 3D modeling highlighted protein-RNA interaction domains within the human prion pseudoknot.
Conclusions:
- Pseudoknots are a conserved feature in many prion mRNAs, potentially acquired early in evolution.
- These structures may influence prion protein translation.
- The repeat region's pseudoknots are implicated in familial Creutzfeldt-Jakob disease.