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Structural implication of splicing stochastics.

Melamud E, Moult J - Nucleic Acids Res. (2009)

Bottom Line: We find that the vast majority of all alternative isoforms result in unstable protein conformations.Alternative splicing in disease-associated genes produces unstable structures just as frequently as all other genes, indicating that selection to reduce the effects of alternative splicing on this set is not especially pronounced.Overall, the properties of alternative spliced proteins are consistent with the outcome of noisy selection of splice sites by splicing machinery.

View Article: PubMed Central - PubMed

Affiliation: Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, 9600 Gudelsky Drive, Rockville, MD 20850, USA. melamud@umbi.umd.edu

ABSTRACT
Even though nearly every human gene has at least one alternative splice form, very little is so far known about the structure and function of resulting protein products. It is becoming increasingly clear that a significant fraction of all isoforms are products of noisy selection of splice sites and thus contribute little to actual functional diversity, and may potentially be deleterious. In this study, we examine the impact of alternative splicing on protein sequence and structure in three datasets: alternative splicing events conserved across multiple species, alternative splicing events in genes that are strongly linked to disease and all observed alternative splicing events. We find that the vast majority of all alternative isoforms result in unstable protein conformations. In contrast to that, the small subset of isoforms conserved across species tends to maintain protein structural integrity to a greater extent. Alternative splicing in disease-associated genes produces unstable structures just as frequently as all other genes, indicating that selection to reduce the effects of alternative splicing on this set is not especially pronounced. Overall, the properties of alternative spliced proteins are consistent with the outcome of noisy selection of splice sites by splicing machinery.

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Comparison between random exon deletions and deletions observed in minor isoforms. Genes are divided into five sets: Random Exon Deletions, Human Only Deletions, Conserved across two, three and four or more species. (A) Number of residues deleted (amino acids). (B) Number of contacts lost. (C) Newly exposed surface area (Å2). (D) Newly exposed hydrophobic surface area (Å2). (E) Distance between Cα atoms at the ends of a deletion (Å). (F) Number of EST sequences that support the alternative splicing. For all the structural properties, the random and all human distributions are very similar, whereas minor isoforms found in multiple species exhibit more conservative structural changes.
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Figure 7: Comparison between random exon deletions and deletions observed in minor isoforms. Genes are divided into five sets: Random Exon Deletions, Human Only Deletions, Conserved across two, three and four or more species. (A) Number of residues deleted (amino acids). (B) Number of contacts lost. (C) Newly exposed surface area (Å2). (D) Newly exposed hydrophobic surface area (Å2). (E) Distance between Cα atoms at the ends of a deletion (Å). (F) Number of EST sequences that support the alternative splicing. For all the structural properties, the random and all human distributions are very similar, whereas minor isoforms found in multiple species exhibit more conservative structural changes.

Mentions: The distributions of various structural features are shown in Figure 7. The random and full human-only sets have very similar distributions for all structural properties. We conclude from this that the large majority of alternatively spliced deletions, on the one hand, result in the production of unstable protein folds. On the other hand, it is immediately obvious that deletions that are conserved across multiple species tend to remove fewer residues, have a smaller end-to-end distance, lose fewer contacts and expose less total and hydrophobic surface area. That is, conserved deletions also tend to be conservative in term of structural impact, supporting the view that these sets are enriched for function compared with unconserved events.Figure 7.


Structural implication of splicing stochastics.

Melamud E, Moult J - Nucleic Acids Res. (2009)

Comparison between random exon deletions and deletions observed in minor isoforms. Genes are divided into five sets: Random Exon Deletions, Human Only Deletions, Conserved across two, three and four or more species. (A) Number of residues deleted (amino acids). (B) Number of contacts lost. (C) Newly exposed surface area (Å2). (D) Newly exposed hydrophobic surface area (Å2). (E) Distance between Cα atoms at the ends of a deletion (Å). (F) Number of EST sequences that support the alternative splicing. For all the structural properties, the random and all human distributions are very similar, whereas minor isoforms found in multiple species exhibit more conservative structural changes.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2724273&req=5

Figure 7: Comparison between random exon deletions and deletions observed in minor isoforms. Genes are divided into five sets: Random Exon Deletions, Human Only Deletions, Conserved across two, three and four or more species. (A) Number of residues deleted (amino acids). (B) Number of contacts lost. (C) Newly exposed surface area (Å2). (D) Newly exposed hydrophobic surface area (Å2). (E) Distance between Cα atoms at the ends of a deletion (Å). (F) Number of EST sequences that support the alternative splicing. For all the structural properties, the random and all human distributions are very similar, whereas minor isoforms found in multiple species exhibit more conservative structural changes.
Mentions: The distributions of various structural features are shown in Figure 7. The random and full human-only sets have very similar distributions for all structural properties. We conclude from this that the large majority of alternatively spliced deletions, on the one hand, result in the production of unstable protein folds. On the other hand, it is immediately obvious that deletions that are conserved across multiple species tend to remove fewer residues, have a smaller end-to-end distance, lose fewer contacts and expose less total and hydrophobic surface area. That is, conserved deletions also tend to be conservative in term of structural impact, supporting the view that these sets are enriched for function compared with unconserved events.Figure 7.

Bottom Line: We find that the vast majority of all alternative isoforms result in unstable protein conformations.Alternative splicing in disease-associated genes produces unstable structures just as frequently as all other genes, indicating that selection to reduce the effects of alternative splicing on this set is not especially pronounced.Overall, the properties of alternative spliced proteins are consistent with the outcome of noisy selection of splice sites by splicing machinery.

View Article: PubMed Central - PubMed

Affiliation: Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, 9600 Gudelsky Drive, Rockville, MD 20850, USA. melamud@umbi.umd.edu

ABSTRACT
Even though nearly every human gene has at least one alternative splice form, very little is so far known about the structure and function of resulting protein products. It is becoming increasingly clear that a significant fraction of all isoforms are products of noisy selection of splice sites and thus contribute little to actual functional diversity, and may potentially be deleterious. In this study, we examine the impact of alternative splicing on protein sequence and structure in three datasets: alternative splicing events conserved across multiple species, alternative splicing events in genes that are strongly linked to disease and all observed alternative splicing events. We find that the vast majority of all alternative isoforms result in unstable protein conformations. In contrast to that, the small subset of isoforms conserved across species tends to maintain protein structural integrity to a greater extent. Alternative splicing in disease-associated genes produces unstable structures just as frequently as all other genes, indicating that selection to reduce the effects of alternative splicing on this set is not especially pronounced. Overall, the properties of alternative spliced proteins are consistent with the outcome of noisy selection of splice sites by splicing machinery.

Show MeSH
Related in: MedlinePlus