Functional diversity of intrinsically disordered proteins and their structural heterogeneity: Protein structure-function continuum

Abstract

The fact that protein universe is enriched in intrinsic disorder is an accepted truism now. It is also recognized that the phenomenon of protein intrinsic disorder contains keys to answer numerous questions that do not have obvious solutions within the classic "lock-and-key"-based structure-function paradigm. In fact, reality is much more complex than the traditional "one-gene - one-protein - one-function" model, as many (if not most) proteins are multifunctional. This multifunctionality is commonly rooted in the presence of the intrinsically disordered or structurally flexible regions in a protein. Here, in addition to various events at the DNA (genetic variations), mRNA (alternative splicing, alternative promoter usage, alternative initiation of translation, and mRNA editing), and protein levels (post-translational modifications), intrinsic disorder and protein functionality are crucial for generation of proteoforms, which are functionally and structurally different protein forms produced from a single gene. Therefore, since a given protein exists as a dynamic conformational ensemble containing multiple proteoforms characterized by a broad spectrum of structural features and possessing various functional potentials, "protein structure-function continuum" model represents a more realistic way to correlate protein structure and function.

Keywords: Alternative splicing; Induced fit; Intrinsically disordered protein; Intrinsically disordered region; Lock-and-key; Multifunctionality; Posttranslational modification; Protein interactions; Proteoform; Structure-function continuum.