Many proteins, including at least 2/3 of the protein structures in the Protein Data Bank, contain regions that lack specific 3-D structure; indeed some proteins lack specific 3-D structure in their entireties under physiological conditions and yet carry out function as indicated by appropriate biochemical assays.  Such proteins and regions have been called natively unfolded, intrinsically unstructured, naturally disordered, and rheomorphic, and various combinations of these terms among others.

Starting in 1996, we began to explore the prediction of structured and disordered regions from amino acid sequence.  This is distinct from the prediction of irregular (also called random coil) regions.  Disorder predictions by us and others suggest that a large fraction of eukaryotic proteins contain significant-sized regions of disorder.  Intrinsic disorder is found to be commonly used in cell signaling, with disorder-to-order-transitions upon binding having at least two advantages:  1) the ability to bind with high specificity coupled with weak affinity due to the flexibility in the unbound state;  and 2) the ability to bind to two or more partners due to plasticity in the bound state.

Alternative splicing is very common in multicellular eukaryotes but rare or perhaps non-existent in single-cell eukaryotes.  The RNA removed by alternative splicing is found to code for regions of intrinsic disorder significantly more often than for regions of structure.  Given that signaling segments in regions of disorder are formed from small numbers of contiguous amino acids, and given that many disordered regions have been shown to contain many signaling and regulatory segments in tandem, alternative splicing within regions of disorder provides a simple method for bringing about regulatory and signaling diversity.

We propose that the combination of alternative splicing plus intrinsic disorder provided a means to “try out” alternative regulatory pathways, thus enabling the evolution of differentiated cells.

Those interested in this topic are directed to:
Romero, P. R., Zaidi, S., Fang, Y.Y., Uversky, V.N., Radivojac, P., Cortese, M., Strickmeyer, M., Obradovic, Z., and Dunker, A.K.  "Alternative splicing in concert with protein intrinsic disorder enables functional diversity in multicellular organisms." Proc. National  Academy of Science, USA 103: 8390-8395 (2006)