Paradoxes and wonders of intrinsic disorder: Prevalence of exceptionality.

Abstract

This article opens a series of short comments on paradoxes and wonders of the protein intrinsic disorder phenomenon. Here, the “prevalence of exceptionality” paradox is introduced in a form of a brief historical overview that shows a progression in understanding of the natural abundance of intrinsically disordered proteins from the early days, when these biologically active proteins without unique structures were taken as rare exceptions, to the current days, when the prevalence of intrinsically disordered proteins (IDPs) in various proteomes and biological processes is a well-recognized reality. In one of the first systematic works on IDPs published in 1997, Dunker et al. searched PDB for proteins containing at least one intrinsically disordered region (IDR) longer than seven 7 residues. There, IDRs were defined as regions of missing electron density in the corresponding crystal structures (since disorder leads to incoherent X-ray scattering and subsequent absence of electron density in the solved structure), and, depending on their length, were partitioned into short, medium and long data sets, denoted as SIDR (7–21 amino acids), MIDR (22–44 amino acids), and LIDR (45 or more amino acids), respectively. The SIDR dataset contained 38 disordered segments from 34 proteins with 411 disordered amino acids and 11,050 total amino acids; MIDR set contained 22 disordered segments from 20 proteins with 464 disordered amino acids and 4,764 total amino acids; and LIDR set contained 7 regions from 7 proteins with 465 disordered amino acids and 2,069 total amino acids. In the subsequent study, the set of seven 7 LIDR proteins with the X-rayX-ray-characterized regions of disorder was extended to include seven 7 proteins shown to be disordered by NMR, with the total number of disordered residues in that set being 677 amino acids. Uversky et al. compiled a list of 91 IDPs characterized by NMR, circular dichroism or other biophysical techniques. Proteins in that study were completely disordered, belonging to the sub-class of natively unfolded proteins that do not have any (or almost any) residual structure. Those IDPs ranged in length from 49 to 1,827 residues and the total number of disordered residues in that set was 17,318 amino acids. In 2001, it has been reported that the list of experimentally validated IDPs characterized by NMR or X-ray, or circular dichroism can be extended to 150 entries that contained 17,417 disordered residues and a year later, this set was further extended to total 157 proteins with 18,833 disordered residues A subsequent search of X-rayX-ray crystal structures and the literature have further expanded this list to more than 200 proteins that contain disordered regions of 30 consecutive residues or longer as characterized by X-ray crystallography, proteolytic digestion or other physical analyses such as NMR or circular dichroism. Recently, the exhaustive literature analysis revealed that the current list of experimentally validated IDPs includes »1,150 non-redundant proteins (DeForte S., Uversky V.N., manuscript in preparation) Careful analysis and comparison of the non-redundant sets of ordered and disordered proteins (where IDPs/IDRs were characterized by different experimental *Correspondence to: Vladimir N Uversky; E-mail: vuversky@health.usf.edu