Understanding protein non-folding

Abstract

This review describes the family of intrinsically disordered proteins, members of which fail to form rigid 3-D structures under physiological conditions, either along their entire lengths or only in localized regions. Instead, these intriguing proteins/regions exist as dynamic ensembles within which atom positions and backbone Ramachandran angles exhibit extreme temporal fluctuations without specific equilibrium values. Many of these intrinsically disordered proteins are known to carry out important biological functions which, in fact, depend on the absence of specific 3-D structure. The existence of such proteins does not fit the prevailing structure-function paradigm, which states that unique 3-D structure is a prerequisite to function. Thus, the protein structure-function paradigm has to be expanded to include intrinsically disordered proteins and alternative relationships among protein sequence, structure, and function. This shift in the paradigm represents a major breakthrough for biochemistry, biophysics and molecular biology, as it opens new levels of understanding with regard to the complex life of proteins. This review will try to answer the following questions: How were intrinsically disordered proteins discovered? Why don't these proteins fold? What is so special about intrinsic disorder? What are the functional advantages of disordered proteins/regions? What is the functional repertoire of these proteins? What are the relationships between intrinsically disordered proteins and human diseases?

Resilience of death: intrinsic disorder in proteins involved in the programmed cell death

“…Both of these features are typical for IDPs/IDPRs. 24,27 These observations provide further support to the general conclusion of this study that intrinsic disorder is crucial for the regulation and control of all the PCD types. Here, proteins regulating necroptosis seem to be more disordered than protein involved in other types of the controlled cell death.…”

“…24 IDPs are abundant in all proteomes [25][26] and possess a wide spectrum of biological functions that are typically related to regulation, signaling, and control pathways, promote the assembly of supra-molecular complexes, and complement the functions of ordered proteins. 24 IDPs/IDPRs possess complex 'anatomy' (they contain multiple, relatively short functional elements), which contributes to their unique 'physiology' (an ability to be involved in interaction with, regulation of and control by multiple structurally unrelated partners). Functions of IDPs are further controlled by alternative splicing, which generates a set of protein isoforms with a highly diverse set of regulatory elements.…”

Improved tolerance to salt and water stress in Drosophila melanogaster cells conferred by late embryogenesis abundant protein

“…Nevertheless, it is becoming clear that LEA proteins exhibit specific functions at hydration states that most likely lack extensive secondary structure in vivo and thus can operate outside the classic structure-function paradigm (cf. (Uversky and Dunker, 2010)). Creative Activities grants (URSCA) to M.R.M.…”

A pre-structured helix in the intrinsically disordered 4EBP1

“…[1][2][3][4][5] As the eventual function of most (B80%) IDPs is to convey biological signals by binding to various types of target molecules, such as proteins, nucleic acids, metals, or lipids, 1,6,7 delineating their target-binding mechanism is important to clearly understand IDP function. Recent studies illustrate that accurate structural knowledge of IDPs may have immediate consequences even for drug development.…”