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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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Structural isoforms of alternatively spliced human proteins. (A) Structural alignment of the major and minor isoform in the PDZ2 domain of the protein tyrosine phosphatase PTN13_HUMAN. The two splice variants have a different affinity to the tumor suppressor protein APC (35). Isoform 4 has a 5-residue-long insertion (colored bright red) compared to the main isoform. This was the longest insertion in a splice variant in PDB where both variants are ordered at the alternative splice site. (B) The structural alignment of the two isoforms of the hexokinase KHK_HUMAN (PDB codes: 2hqqA, 3b3lA). The minor isoform contains a 44-residue substitution, which represents a paralogous local exon duplication (indicated with solid blue and red colors in 2 hqqA and 3b3lA, respectively). AS of the KHK gene selects either one or the other of two adjacent, homologous 135-bp exons.
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Figure 4: Structural isoforms of alternatively spliced human proteins. (A) Structural alignment of the major and minor isoform in the PDZ2 domain of the protein tyrosine phosphatase PTN13_HUMAN. The two splice variants have a different affinity to the tumor suppressor protein APC (35). Isoform 4 has a 5-residue-long insertion (colored bright red) compared to the main isoform. This was the longest insertion in a splice variant in PDB where both variants are ordered at the alternative splice site. (B) The structural alignment of the two isoforms of the hexokinase KHK_HUMAN (PDB codes: 2hqqA, 3b3lA). The minor isoform contains a 44-residue substitution, which represents a paralogous local exon duplication (indicated with solid blue and red colors in 2 hqqA and 3b3lA, respectively). AS of the KHK gene selects either one or the other of two adjacent, homologous 135-bp exons.

Mentions: The longest insert that has an ordered structure at the site of the insertion in both isoforms is 5 amino acids in the PDZ2 domain of the protein tyrosine phosphatase PTN13_HUMAN where the two splice variants have a different affinity to the tumor suppressor protein APC (35). The structural alignment of the two isoforms is shown in Figure 4A.Figure 4.


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)

Structural isoforms of alternatively spliced human proteins. (A) Structural alignment of the major and minor isoform in the PDZ2 domain of the protein tyrosine phosphatase PTN13_HUMAN. The two splice variants have a different affinity to the tumor suppressor protein APC (35). Isoform 4 has a 5-residue-long insertion (colored bright red) compared to the main isoform. This was the longest insertion in a splice variant in PDB where both variants are ordered at the alternative splice site. (B) The structural alignment of the two isoforms of the hexokinase KHK_HUMAN (PDB codes: 2hqqA, 3b3lA). The minor isoform contains a 44-residue substitution, which represents a paralogous local exon duplication (indicated with solid blue and red colors in 2 hqqA and 3b3lA, respectively). AS of the KHK gene selects either one or the other of two adjacent, homologous 135-bp exons.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 4: Structural isoforms of alternatively spliced human proteins. (A) Structural alignment of the major and minor isoform in the PDZ2 domain of the protein tyrosine phosphatase PTN13_HUMAN. The two splice variants have a different affinity to the tumor suppressor protein APC (35). Isoform 4 has a 5-residue-long insertion (colored bright red) compared to the main isoform. This was the longest insertion in a splice variant in PDB where both variants are ordered at the alternative splice site. (B) The structural alignment of the two isoforms of the hexokinase KHK_HUMAN (PDB codes: 2hqqA, 3b3lA). The minor isoform contains a 44-residue substitution, which represents a paralogous local exon duplication (indicated with solid blue and red colors in 2 hqqA and 3b3lA, respectively). AS of the KHK gene selects either one or the other of two adjacent, homologous 135-bp exons.
Mentions: The longest insert that has an ordered structure at the site of the insertion in both isoforms is 5 amino acids in the PDZ2 domain of the protein tyrosine phosphatase PTN13_HUMAN where the two splice variants have a different affinity to the tumor suppressor protein APC (35). The structural alignment of the two isoforms is shown in Figure 4A.Figure 4.

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