Intrinsically Disordered Proteins: From Sequence and Conformational Properties toward Drug Discovery

Abstract

Structural disorder of functional proteins under physiological conditions is widespread within eukaryotic proteomes. The lack of stable tertiary and secondary structure offers a variety of functional advantages to intrinsically disordered proteins (IDPs): their malleability of interaction with different partners, specific but low-affinity binding, and their fine modulation by post-translational modifications. IDPs are therefore central players in key processes such as cell-cycle control and signal-transduction pathways, and impairment of their function is associated with many disease states such as cancer and neurodegenerative disorders. Fascinating progress in the experimental characterization of IDPs has been made in the last decade, especially in NMR spectroscopy and small-angle X-ray scattering as well as in single-molecule techniques. It has been accompanied by the development of powerful computational tools to translate experimental results in explicit ensemble representations of IDPs. With the aid of bioinformatics tools, these advances have paved the way to targeting IDP interactions in rational drug-discovery projects.

Association Between Foldability and Aggregation Propensity in Small Disulfide-Rich Proteins

“…Cys, Trp, Tyr, Ile, Phe, Val, and Leu are considered orderpromoting residues, as they occur more frequently in ordered than in disordered structural regions (37,72). In addition, in the FoldUnfold scale, Cys has a high mean packing density (42), reflecting that, in protein structures, Cys residues tend to exist in densely packed environments.…”

Druggability of Intrinsically Disordered Proteins

“…Therefore, a possible strategy to target aggregation-prone IDPs implicated in misfolding diseases is to stabilize the protein in conformations that do not readily enable the formation of higher order species. Indeed, recent studies are beginning to suggest that such approaches may be promising (Zhu et al 2013;Toth et al 2014;Dunker and Uversky 2010;Metallo 2010;Rezaei-Ghaleh et al 2012;Uversky 2012).…”

A six-dimensional alpha proton detection-based APSY experiment for backbone assignment of intrinsically disordered proteins

“…Due to their inherent plasticity IDPs are not amenable to structural characterization by X-ray crystallography. This makes NMR spectroscopy the only method that provides residue-specific insights into the conformational ensembles populated by IDPs in solution and their associated exchange dynamics (Jensen et al 2013;Rezaei-Ghaleh et al 2012;Uversky 2002).…”