Is there a biological cost of protein disorder? Analysis of cancer-associated mutations

Abstract

As many diseases can be traced back to altered protein function, studying the effect of genetic variations at the level of proteins can provide a clue to understand how changes at the DNA level lead to various diseases. Cellular processes rely not only on proteins with well-defined structure but can also involve intrinsically disordered proteins (IDPs) that exist as highly flexible ensembles of conformations. Disordered proteins are mostly involved in signaling and regulatory processes, and their functional repertoire largely complements that of globular proteins. However, it was also suggested that protein disorder entails an increased biological cost. This notion was supported by a set of individual IDPs involved in various diseases, especially in cancer, and the increased amount of disorder observed among disease-associated proteins. In this work, we tested if there is any biological risk associated with protein disorder at the level of single nucleotide mutations. Specifically, we analyzed the distribution of mutations within ordered and disordered segments. Our results demonstrated that while neutral polymorphisms were more likely to occur within disordered segments, cancer-associated mutations had a preference for ordered regions. Additionally, we proposed an alternative explanation for the association of protein disorder and the involvement in cancer with the consideration of functional annotations. Individual examples also suggested that although disordered segments are fundamental functional elements, their presence is not necessarily accompanied with an increased mutation rate in cancer. The presented study can help to understand how the different structural properties of proteins influence the consequences of genetic mutations.