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Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
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Functional implications of structural predictions for alternative splice proteins expressed in Her2/neu-induced

Rajasree Menon1, Ambrish Roy, Srayanta Mukherjee

  • 1Center for Computational Medicine and Bioinformatics, University of Michigan, 100 Washtenaw Avenue, Ann Arbor, Michigan 48109-2218, United States. rajmenon@umich.edu

Journal of Proteome Research
|October 19, 2011
PubMed

Insights

Alternative splicing creates diverse protein forms. New computational methods reveal subtle structural differences in these variants, impacting their functions, especially in cancer.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Bioinformatics

Background:

  • Alternative splicing generates protein isoforms with diverse functions from a single gene.
  • Experimental structures of protein splice isoforms are scarce, and traditional modeling struggles with high sequence identity.
  • Understanding structural variations in splice isoforms is crucial for deciphering protein function and disease mechanisms.

Purpose of the Study:

  • To assess the utility of the I-TASSER structure prediction tool for analyzing structural and functional consequences of alternative splicing.
  • To investigate structural differences in cancer-related protein splice variants.
  • To explore the structural impact of alternative splicing in proteins overexpressed in a breast cancer model.

Main Methods:

  • Benchmarking I-TASSER against experimentally solved structures for seven protein splice isoform pairs.
  • Utilizing I-TASSER to model three cancer-related variant pairs with known opposing functions.
  • Applying I-TASSER to model five overexpressed splice variants (anxa6, calu, cdc42, ptbp1, tax1bp3) in a mouse breast cancer model.

Main Results:

  • I-TASSER successfully modeled all seven benchmarked protein splice isoform pairs.
  • Distinct structural differences were identified in functionally relevant regions of cancer-related variant pairs.
  • Significant structural variations were observed in biologically important regions of five overexpressed splice variants, despite high sequence identity (>75%).

Conclusions:

  • The I-TASSER pipeline is effective for predicting structures of alternative splice variants.
  • Alternative splicing can induce subtle yet functionally significant structural changes in proteins.
  • Integrating computational structure prediction with proteomic data offers a powerful approach to study splice variants in diseases like cancer.

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