[Abstract unavailable

The experimental material accumulated in the literature on the conformational behavior of intrinsically unstructured (natively unfolded) proteins was analyzed. Results of this analysis showed that these proteins do not possess uniform structural properties, as expected for members of a single thermodynamic entity. Rather, these proteins may be divided into two structurally different groups: intrinsic coils, and premolten globules. Proteins from the first group have hydrodynamic dimensions typical of random coils in poor solvent and do not possess any (or almost any) ordered secondary structure. Proteins from the second group are essentially more compact, exhibiting some amount of residual secondary structure, although they are still less dense than native or molten globule proteins. An important feature of the intrinsically unstructured proteins is that they undergo disorder-order transition during or prior to their biological function. In this respect, the Protein Quartet model, with function arising from four specific conformations (ordered forms, molten globules, premolten globules, and random coils) and transitions between any two of the states, is discussed.Keywords: Intrinsically unfolded protein; intrinsically disordered protein; unfolded protein; molten globule; premolten globule; partially folded intermediate; random coil; conformational transition This review introduces an intriguing protein family of natively unfolded proteins, whose existence questions one of the cornerstones in protein biology, chemistry and physics, that is, the structure-function paradigm. This concept claims that a specific function of a protein is determined by its unique and rigid three-dimensional (3D) structure. This idea, formulated more than 100 years ago as a lock-and-key model for explaining the amazing specificity of the enzymatic hydrolysis of glucosides (Fischer 1894), proved to be extremely fruitful. Figuratively speaking, the protein structure-function paradigm may be considered as the big bang, creating the universe of modern protein science. Figure 1 attempts to illustrate the most obvious scientific consequences of this concept.However, a reappraisal of the protein structure-function paradigm is now warranted based on systematic studies of intrinsically unfolded/disordered proteins (Wright and Dyson 1999;Dunker et al. 2001;Uversky 2002). There are two major reasons for such a reappraisal: the results of the amino acid sequence analyses and the accumulation of experimental evidence for the existence of a rather large amount of protein domains and even entire proteins, lacking ordered structure under physiological conditions. Intriguingly, both of these sets of evidences were gathered using scientific concepts and approaches originating from the protein structure-function paradigm, namely, proteomics and protein self-organization (see Fig. 1).

Figure 1. Structured domains and intrinsically disordered regions (IDRs) are two fundamental classes of functional building blocks of proteins. The synergy between disordered regions and structured domains increases the functional versatility of proteins. Adapted with permission from ref 50.