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. 2005 Dec 27;102(52):18920-5.
doi: 10.1073/pnas.0506770102. Epub 2005 Dec 14.

Structural genomics analysis of alternative splicing and application to isoform structure modeling

Peng Wang  1 , Bo Yan, Jun-Tao Guo, Chindo Hicks, Ying Xu
Affiliations

Structural genomics analysis of alternative splicing and application to isoform structure modeling

Peng Wang et al. Proc Natl Acad Sci U S A. .

Abstract

Alternative splicing is a sophisticated nuclear process that regulates gene expression. It represents an important mechanism for enhancing the functional diversity of proteins. Our current knowledge of alternatively spliced variants is derived mainly from mRNA transcripts, and very little is known about their protein tertiary structures. We carried out a large-scale analysis of known alternatively spliced variants at both protein sequence and structure levels and have shown that threading is, in general, a viable approach for modeling structures of alternatively spliced variants. An examination of alternative splicing at the protein sequence level revealed that the size of splicing events follows the power law distribution and the majority of splicing isoforms harbor only one or two alternations. We examined alternative splicing in the context of protein 3D structures and found that the boundaries of alternative splicing events generally happen in coil regions of secondary structures and exposed residues and the majority of the sequences involved in splicing are located on the surface of proteins. In light of these findings, we then proceeded to demonstrate that threading represents a useful tool for structure prediction of alternative splicing isoforms and addressed the fold stability issue of threading-based structure prediction by molecular dynamics simulation. Our analysis and the insights gained have helped to establish a viable method for structure prediction of alternatively spliced isoforms at the genome scale.

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Figures

Fig. 1.
Fig. 1.
Distribution of splicing events. (a) The size of splicing events follows the power law distribution. The size of alternative splicing events and the number of corresponding events are plotted on a log vs. log graph. The majority of alternative splicing events are of small size, and events become rare as size increases. For events with size >20, they appear to follow the power law distribution (power law factor –1.07, linear regression adjusted R2 0.75). (b) The number of isoforms decreases exponentially as the number of splicing events per isoform increases. The log of the number of splicing isoforms has a strong linear relationship with the number of splicing events per isoform with adjusted R2 0.93.
Fig. 2.
Fig. 2.
Distribution of protein fragments involved in splicing on the surface and in the interior of protein structures. The fragments were partitioned according to their sizes. The filled bars show the frequencies of fragments mapped to protein surfaces only, and the empty bars show the frequencies of fragments mapped to both surface and interior. (a) Substitution events. (b) Deletions.
Fig. 3.
Fig. 3.
The threading z score of splicing isoforms was inversely correlated with the percentage of the core secondary structure elements altered. Splicing isoforms were partitioned into three types: isoforms with single substitution (a), isoforms with single deletion (b), and isoforms with multiple alternations (c). The threading z score of splicing isoforms was then plotted against the percentage of CSSEs altered by the isoforms.
Fig. 4.
Fig. 4.
Molecular dynamics simulation of O64636-2. (a) The structure of O64636-1 is shown in with the region substituted or deleted colored in red. (b) The backbone rms deviation (RMSD) of O64636-2 from initial structure as a function of time. (c) The alignment of O64636-2 structures at 0 ns (blue) and 3 ns (red) of simulation. The transformation matrix used in alignment was calculated by using only helices highlighted in the red box in the O64636-2 structure to demonstrate the movement of the O64636-2 structure highlighted in the blue box. (d) The three helices and two strands highlighted in blue box are aligned. The structure at 0-ns simulation is colored blue, and the structure at 3-ns simulation is colored red.
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References

    1. Black, D. L. (2003) Annu. Rev. Biochem. 72, 291–336. - PubMed
    1. Brett, D., Hanke, J., Lehmann, G., Haase, S., Delbruck, S., Krueger, S., Reich, J. & Bork, P. (2000) FEBS Lett. 474, 83–86. - PubMed
    1. Johnson, J. M., Castle, J., Garrett-Engele, P., Kan, Z., Loerch, P. M., Armour, C. D., Santos, R., Schadt, E. E., Stoughton, R. & Shoemaker, D. D. (2003) Science 302, 2141–2144. - PubMed
    1. Xu, X., Yang, D., Ding, J. H., Wang, W., Chu, P. H., Dalton, N. D., Wang, H. Y., Bermingham, J. R., Jr., Ye, Z., Liu, F., et al. (2005) Cell 120, 59–72. - PubMed
    1. Johnson, C. R. & Jarvis, W. D. (2004) Apoptosis 9, 423–427. - PubMed

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