The evolutionary origins of cell type diversification and the role of intrinsically disordered proteins

The evolution of complex multicellular life forms occurred multiple times and was attended by cell type specialization. We review seven lines of evidence indicating that intrinsically disordered/ductile proteins (IDPs) played a significant role in the evolution of multicellularity and cell type specification: (i) most eukaryotic transcription factors (TFs) and multifunctional enzymes contain disproportionately long IDP sequences (≥30 residues in length), whereas highly conserved enzymes are normally IDP region poor; (ii) ~80% of the proteome involved in development are IDPs; (iii) the majority of proteins undergoing alternative splicing (AS) of pre-mRNA contain significant IDP regions; (iv) proteins encoded by DNA regions flanking crossing-over 'hot spots' are significantly enriched in IDP regions; (v) IDP regions are disproportionately subject to combinatorial post-translational modifications (PTMs) as well as AS; (vi) proteins involved in transcription and RNA processing are enriched in IDP regions; and (vii) a strong positive correlation exists between the number of different cell types and the IDP proteome fraction across a broad spectrum of uni- and multicellular algae, plants, and animals. We argue that the multifunctionalities conferred by IDPs and the disproportionate involvement of IDPs with AS and PTMs provided a IDP-AS-PTM 'motif' that significantly contributed to the evolution of multicellularity in all major eukaryotic lineages.