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Verification of alternative splicing variants based on domain integrity, truncation length and intrinsic protein disorder.

Hegyi H, Kalmar L, Horvath T, Tompa P - Nucleic Acids Res. (2010)

Bottom Line: However, for 4000 human proteins in PDB, only 14 human proteins have structures of at least two alternative isoforms.We found that strict rules govern the selection of alternative splice variants aimed to preserve the integrity of globular domains: alternative splice sites (i) tend to avoid globular domains or (ii) affect them only marginally or (iii) tend to coincide with a location where the exposed hydrophobic surface is minimal or (iv) the protein is disordered.These observations provide the basis for a prediction method (currently under development) to predict the viability of splice variants.

View Article: PubMed Central - PubMed

Affiliation: Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, PO Box 7, 1518 Budapest, Hungary. hegyi@enzim.hu

ABSTRACT
According to current estimations ∼95% of multi-exonic human protein-coding genes undergo alternative splicing (AS). However, for 4000 human proteins in PDB, only 14 human proteins have structures of at least two alternative isoforms. Surveying these structural isoforms revealed that the maximum insertion accommodated by an isoform of a fully ordered protein domain was 5 amino acids, other instances of domain changes involved intrinsic structural disorder. After collecting 505 minor isoforms of human proteins with evidence for their existence we analyzed their length, protein disorder and exposed hydrophobic surface. We found that strict rules govern the selection of alternative splice variants aimed to preserve the integrity of globular domains: alternative splice sites (i) tend to avoid globular domains or (ii) affect them only marginally or (iii) tend to coincide with a location where the exposed hydrophobic surface is minimal or (iv) the protein is disordered. We also observed an inverse correlation between the domain fraction lost and the full length of the minor isoform containing the domain, possibly indicating a buffering effect for the isoform protein counteracting the domain truncation effect. These observations provide the basis for a prediction method (currently under development) to predict the viability of splice variants.

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CHASA-diff analysis of 1c47 phosphoglucomutase-1 with SCOP domain boundaries indicated by vertical lines. The domain boundaries separating the four domains in the PDB structure coincide with minima in CHASA-diff, indicating relatively small hydrophobic surface areas.
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Figure 5: CHASA-diff analysis of 1c47 phosphoglucomutase-1 with SCOP domain boundaries indicated by vertical lines. The domain boundaries separating the four domains in the PDB structure coincide with minima in CHASA-diff, indicating relatively small hydrophobic surface areas.

Mentions: We also determined the hydrophobic surface values of the actual ‘subdomains’ of the PDB chain in question by gradually truncating it (removing the coordinates) in steps of 5, 10 or 20 residues, depending on the original length of the chain (<101 residues, between 101 and 300, or >300 residues, respectively). We calculated the difference between the two values at each truncation point we named CHASA-diff. A typical graph of the differing values is shown for 1c47 chain A (Figure 5).


Verification of alternative splicing variants based on domain integrity, truncation length and intrinsic protein disorder.

Hegyi H, Kalmar L, Horvath T, Tompa P - Nucleic Acids Res. (2010)

CHASA-diff analysis of 1c47 phosphoglucomutase-1 with SCOP domain boundaries indicated by vertical lines. The domain boundaries separating the four domains in the PDB structure coincide with minima in CHASA-diff, indicating relatively small hydrophobic surface areas.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3045584&req=5

Figure 5: CHASA-diff analysis of 1c47 phosphoglucomutase-1 with SCOP domain boundaries indicated by vertical lines. The domain boundaries separating the four domains in the PDB structure coincide with minima in CHASA-diff, indicating relatively small hydrophobic surface areas.
Mentions: We also determined the hydrophobic surface values of the actual ‘subdomains’ of the PDB chain in question by gradually truncating it (removing the coordinates) in steps of 5, 10 or 20 residues, depending on the original length of the chain (<101 residues, between 101 and 300, or >300 residues, respectively). We calculated the difference between the two values at each truncation point we named CHASA-diff. A typical graph of the differing values is shown for 1c47 chain A (Figure 5).

Bottom Line: However, for 4000 human proteins in PDB, only 14 human proteins have structures of at least two alternative isoforms.We found that strict rules govern the selection of alternative splice variants aimed to preserve the integrity of globular domains: alternative splice sites (i) tend to avoid globular domains or (ii) affect them only marginally or (iii) tend to coincide with a location where the exposed hydrophobic surface is minimal or (iv) the protein is disordered.These observations provide the basis for a prediction method (currently under development) to predict the viability of splice variants.

View Article: PubMed Central - PubMed

Affiliation: Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, PO Box 7, 1518 Budapest, Hungary. hegyi@enzim.hu

ABSTRACT
According to current estimations ∼95% of multi-exonic human protein-coding genes undergo alternative splicing (AS). However, for 4000 human proteins in PDB, only 14 human proteins have structures of at least two alternative isoforms. Surveying these structural isoforms revealed that the maximum insertion accommodated by an isoform of a fully ordered protein domain was 5 amino acids, other instances of domain changes involved intrinsic structural disorder. After collecting 505 minor isoforms of human proteins with evidence for their existence we analyzed their length, protein disorder and exposed hydrophobic surface. We found that strict rules govern the selection of alternative splice variants aimed to preserve the integrity of globular domains: alternative splice sites (i) tend to avoid globular domains or (ii) affect them only marginally or (iii) tend to coincide with a location where the exposed hydrophobic surface is minimal or (iv) the protein is disordered. We also observed an inverse correlation between the domain fraction lost and the full length of the minor isoform containing the domain, possibly indicating a buffering effect for the isoform protein counteracting the domain truncation effect. These observations provide the basis for a prediction method (currently under development) to predict the viability of splice variants.

Show MeSH
Related in: MedlinePlus