title: Functional implications of structural predictions for alternative splice proteins expressed in Her2/neu-induced breast cancers.
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.
authors: Center for Computational Medicine and Bioinformatics, University of Michigan, 100 Washtenaw Avenue, Ann Arbor, Michigan 48109-2218, United States. rajmenon@umich.edu
authors: Rajasree
authors: R
authors: Menon
authors: Ambrish
authors: A
authors: Roy
authors: Srayanta
authors: S
authors: Mukherjee
authors: Saveliy
authors: S
authors: Belkin
authors: Yang
authors: Y
authors: Zhang
authors: Gilbert S
authors: GS
authors: Omenn
mesh_terms: D000465:Algorithms; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D017317:Annexin A6 / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019295:Computational Biology / Q000379:methods; D030562:Databases, Protein; D005260:Female; D018734:Genes, erbB-2; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D038941:Polypyrimidine Tract-Binding Protein / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D040901:Proteomics / Q000379:methods*; D013329:Structure-Activity Relationship; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D017317:Annexin A6; D002135:Calcium-Binding Proteins; C107182:Calu protein, mouse; D020033:Protein Isoforms; D038941:Polypyrimidine Tract-Binding Protein; D020764:cdc42 GTP-Binding Protein