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Title: Functional implications of structural predictions for alternative splice proteins expressed in Her2/neu-induced breast cancers.

Authors: Menon, Rajasree; Roy, Ambrish; Mukherjee, Srayanta; Belkin, Saveliy; Zhang, Yang; Omenn, Gilbert S

Published In J Proteome Res, (2011 Dec 02)

Abstract: Alternative splicing allows a single gene to generate multiple mRNA transcripts, which can be translated into functionally diverse proteins. However, experimentally determined structures of protein splice isoforms are rare, and homology modeling methods are poor at predicting atomic-level structural differences because of high sequence identity. Here we exploit the state-of-the-art structure prediction method I-TASSER to analyze the structural and functional consequences of alternative splicing of proteins differentially expressed in a breast cancer model. We first successfully benchmarked the I-TASSER pipeline for structure modeling of all seven pairs of protein splice isoforms, which are known to have experimentally solved structures. We then modeled three cancer-related variant pairs reported to have opposite functions. In each pair, we observed structural differences in regions where the presence or absence of a motif can directly influence the distinctive functions of the variants. Finally, we applied the method to five splice variants overexpressed in mouse Her2/neu mammary tumor: anxa6, calu, cdc42, ptbp1, and tax1bp3. Despite >75% sequence identity between the variants, structural differences were observed in biologically important regions of these protein pairs. These results demonstrate the feasibility of integrating proteomic analysis with structure-based conformational predictions of differentially expressed alternative splice variants in cancers and other conditions.

PubMed ID: 22003824 Exiting the NIEHS site

MeSH Terms: Algorithms; Alternative Splicing*; Amino Acid Sequence; Animals; Annexin A6/genetics; Annexin A6/metabolism; Calcium-Binding Proteins/genetics; Calcium-Binding Proteins/metabolism; Computational Biology/methods; Databases, Protein; Female; Genes, erbB-2*; Humans; Mammary Neoplasms, Experimental/genetics; Mammary Neoplasms, Experimental/metabolism*; Mammary Neoplasms, Experimental/pathology; Mice; Models, Molecular; Molecular Sequence Data; Polypyrimidine Tract-Binding Protein/genetics; Polypyrimidine Tract-Binding Protein/metabolism; Protein Conformation; Protein Isoforms/genetics; Protein Isoforms/metabolism; Proteomics/methods*; Structure-Activity Relationship; cdc42 GTP-Binding Protein/genetics; cdc42 GTP-Binding Protein/metabolism

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