Origins of Myc proteins--using intrinsic protein disorder to trace distant relatives.

Mammalian Myc proteins are important determinants of cell proliferation as well as the undifferentiated state of stem cells and their activity is frequently deregulated in cancer. Based mainly on conservation in the C-terminal DNA-binding and dimerization domain, Myc-like proteins have been reported in many simpler organisms within and outside the Metazoa but they have not been found in fungi or plants. Several important signature motifs defining mammalian Myc proteins are found in the N-terminal domain but the extent to which these are found in the Myc-like proteins from simpler organisms is not well established. The extent of N-terminal signature sequence conservation would give important insights about the evolution of Myc proteins and their current function in mammalian physiology and disease. In a systematic study of Myc-like proteins we show that N-terminal signature motifs are not readily detectable in individual Myc-like proteins from invertebrates but that weak similarities to Myc boxes 1 and 2 can be found in the N-termini of the simplest Metazoa as well as the unicellular choanoflagellate, Monosiga brevicollis, using multiple protein alignments. Phylogenetic support for the connections of these proteins to established Myc proteins is however poor. We show that the pattern of predicted protein disorder along the length of Myc proteins can be used as a complementary approach to making dendrograms of Myc proteins that aids the classification of Myc proteins. This suggests that the pattern of disorder within Myc proteins is more conserved through evolution than their amino acid sequence. In the disorder-based dendrograms the Myc-like proteins from simpler organisms, including M. brevicollis, are connected to established Myc proteins with a higher degree of certainty. Our results suggest that protein disorder based dendrograms may be of general significance for studying distant relationships between proteins, such as transcription factors, that have high levels of intrinsic disorder.