The protein kingdom extended: ordered and intrinsically disordered proteins, their folding, supramolecular complex formation, and aggregation

Abstract

The native state of a protein is usually associated with a compact globular conformation possessing a rigid and highly ordered structure. At the turn of the last century certain studies arose which concluded that many proteins cannot, in principle, form a rigid globular structure in an aqueous environment, but they are still able to fulfill their specific functions--i.e., they are native. The existence of the disordered regions allows these proteins to interact with their numerous binding partners. Such interactions are often accompanied by the formation of complexes that possess a more ordered structure than the original components. The functional diversity of these proteins, combined with the variability of signals related to the various intra- and intercellular processes handled by these proteins and their capability to produce multi-variant and multi-directional responses allow them to form a unique regulatory net in a cell. The abundance of disordered proteins inside the cell is precisely controlled at the synthesis and clearance levels as well as via interaction with specific binding partners and post-translational modifications. Another recently recognized biologically active state of proteins is the functional amyloid. The formation of such functional amyloids is tightly controlled and therefore differs from the uncontrolled formation of pathogenic amyloids which are associated with the pathogenesis of several conformational diseases, the development of which is likely to be determined by the failures of the cellular regulatory systems rather than by the formation of the proteinaceous deposits and/or by the protofibril toxicity.

Figure 1

The energy landscape model illustrating the formation of native globular and intrinsically disordered proteins, supramolecular complexes, amorphous aggregates and amyloid fibrils. A. Globular proteins. In the globular protein folding, the increase in the free energy associated with the folding-induced entropy decrease is compensated by the formation of specific intramolecular contacts. Local free energy minima at the energy landscape correspond to the formation of partially folded intermediates (1, 2). Intermolecular contacts of partially folded protein molecules can result in the formation of oligomers, amorphous aggregates or amyloid fibrils B. Intrinsically disordered proteins. Many native proteins with distinctive biological functions lack compact globular structure in aqueous solutions. Disordered segments of these proteins can gain ordered structure at the interaction with specific binding partners in a case if the free energy of such complexes is lower than the free energies of the intrinsically disordered protein and its partner. The propensity of native completely or partially disordered proteins to interact with various partners determines their biological functions in recognition of various binding partners (Ligands, nucleic acids and other proteins), in regulation of almost all cellular processes, and in signal transduction. In contrast to the folded globular proteins which have to unfold to become amyloidogenic, disordered proteins seem to be always ready for such intermolecular interactions. 1, 2, and 3 represents native complexes of intrinsically disordered proteins with various partners. This figure is based on the energy funnel model developed for globular proteins (Jahn and Radford, 2005; Schultz, 2000).

Figure 2

The model of sequential actin folding on the chaperonin CCT. Greek letters denote CCT subunits; small (S) and large (L) domains of actin are shown as cylinders with the corresponding letters. Actin structure corresponding to the each folding step is shown to the right. Sites of interaction with CCT are shown in green. Green arrows indicate actin site(s) that work at the given stage. PFD-actin is a complex of actin with prefolding. Reproduced from (Neirynck et al., 2006) with the permission from authors.