Protein disorder — a breakthrough invention of evolution?

As an operational definition, we refer to regions in proteins that do not adopt regular three-dimensional structures in isolation, as disordered regions. An antipode to disorder would be ‘well-structured’ rather than ‘ordered’. Here, we argue for the following three hypotheses. Firstly, it is more useful to picture disorder as a distinct phenomenon in structural biology than as an extreme example of protein flexibility. Secondly, there are many very different flavors of protein disorder, nevertheless, it seems advantageous to portray the universe of all possible proteins in terms of two main types: well-structured, disordered. There might be a third type ‘other’ but we have so far no positive evidence for this. Thirdly, nature uses protein disorder as a tool to adapt to different environments. Protein disorder is evolutionarily conserved and this maintenance of disorder is highly nontrivial. Increasingly integrating protein disorder into the toolbox of a living cell was a crucial step in the evolution from simple bacteria to complex eukaryotes. We need new advanced computational methods to study this new milestone in the advance of protein biology.

► Well-structured and disordered regions occupy different regions in the protein universe and both differ from random.
► It seems useful to see protein disorder as a unique aspect of protein structure rather than structural flexibility.
► Although the term protein disorder describes a variety of features, each shares the label disorder.
► Protein disorder is often surprisingly conserved in evolution and serves as its building block.
► We need better experimental and computational methods to handle protein disorder to better understand its role in biology.