Intrinsic structural disorder confers cellular viability on oncogenic fusion proteins.

TitleIntrinsic structural disorder confers cellular viability on oncogenic fusion proteins.
Publication TypeJournal Article
Year of Publication2009
AuthorsHegyi, H., L. Buday, and P. Tompa
JournalPLoS Comput Biol
Date Published2009 Oct
Type of Articleidp
KeywordsAlgorithms, Cell Survival, Cell Transformation, Neoplastic, Chromosome Breakage, Computational Biology, Computer Simulation, Humans, Logistic Models, Models, Molecular, Oncogene Proteins, Fusion, Oncogenes, Protein Conformation, Protein Folding, Translocation, Genetic

Chromosomal translocations, which often generate chimeric proteins by fusing segments of two distinct genes, represent the single major genetic aberration leading to cancer. We suggest that the unifying theme of these events is a high level of intrinsic structural disorder, enabling fusion proteins to evade cellular surveillance mechanisms that eliminate misfolded proteins. Predictions in 406 translocation-related human proteins show that they are significantly enriched in disorder (43.3% vs. 20.7% in all human proteins), they have fewer Pfam domains, and their translocation breakpoints tend to avoid domain splitting. The vicinity of the breakpoint is significantly more disordered than the rest of these already highly disordered fusion proteins. In the unlikely event of domain splitting in fusion it usually spares much of the domain or splits at locations where the newly exposed hydrophobic surface area approximates that of an intact domain. The mechanisms of action of fusion proteins suggest that in most cases their structural disorder is also essential to the acquired oncogenic function, enabling the long-range structural communication of remote binding and/or catalytic elements. In this respect, there are three major mechanisms that contribute to generating an oncogenic signal: (i) a phosphorylation site and a tyrosine-kinase domain are fused, and structural disorder of the intervening region enables intramolecular phosphorylation (e.g., BCR-ABL); (ii) a dimerisation domain fuses with a tyrosine kinase domain and disorder enables the two subunits within the homodimer to engage in permanent intermolecular phosphorylations (e.g., TFG-ALK); (iii) the fusion of a DNA-binding element to a transactivator domain results in an aberrant transcription factor that causes severe misregulation of transcription (e.g. EWS-ATF). Our findings also suggest novel strategies of intervention against the ensuing neoplastic transformations.

Alternate JournalPLoS Comput. Biol.
PubMed ID19888473
PubMed Central IDPMC2768585