Peter Tompa
Institute of Enzymology, Hungarian Academy of Sciences, Budapest, Hungary
Structural disorder of proteins defies the classical structure-function paradigm and is at the forefront of current structural and molecular biology research [1, 2]. Here we show that bioinformatics [3], one of the most powerful tools for studying this structural phenomenon, has provided evidence that disorder is widespread in eukaryotic proteomes and correlates with important regulatory functions, due to which it is also often involved in disease.
In my talk I will survey the role of bioinformatics in the research of disordered proteins, focusing on recent results on its role in the viability of proteins that arise suddenly and unexpectedly in the cell, either due to chromosomal translocations [4] or a shift in the translation frame caused by alternative splicing (AS) [5].
Chromosomal translocations give rise to oncogenic protein chimeras in cancer, whereas frameshift in AS causes two distinct protein products to arise from the same coding region. By analyzing 406 translocation-related human proteins, such as BCR-ABL, we have shown that they are significantly enriched in disorder (43.3% vs. 20.7% in all human proteins), in particular around the breakpoint. AS was approached by selecting 99 human genes with dual coding splice variants, in the case of which the average disorder increases from 22.2% in the ancestral frame to 58.2% in the derived frame.
These results suggest that structural disorder enables aberrant protein products to exist in the cell without the involvement of a lengthy evolutionary selection procedure. The evolutionary, functional and pathological implications of this observation will be discussed in detail.
References
1. Dyson HJ & Wright PE (2005) Intrinsically unstructured proteins and their functions. Nat Rev Mol Cell Biol 6, 197-208.
2. Tompa P (2009) Structure and function of intrinsically disordered proteins CRC Press (Taylor and Francis Group), Boca Raton, FL.
3. He B, Wang K, Liu Y, Xue B, Uversky VN & Dunker AK (2009) Predicting intrinsic disorder in proteins: an overview. Cell Res.
4. Hegyi H, Buday L & Tompa P (2009) Intrinsic structural disorder confers cellular viability on oncogenic fusion proteins. PLoS Comput Biol 5, e1000552.
5. Kovacs E, Tompa P, Liliom K & Kalmar L (2010) Dual coding in alternative reading frames correlates with intrinsic protein disorder. Proc Natl Acad Sci U S A 107, 5429-5434.
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