Protein flexibility, not disorder, is intrinsic to molecular recognition

Abstract

An 'intrinsically disordered protein' (IDP) is assumed to be unfolded in the cell and perform its biological function in that state. We contend that most intrinsically disordered proteins are in fact proteins waiting for a partner (PWPs), parts of a multi-component complex that do not fold correctly in the absence of other components. Flexibility, not disorder, is an intrinsic property of proteins, exemplified by X-ray structures of many enzymes and protein-protein complexes. Disorder is often observed with purified proteins in vitro and sometimes also in crystals, where it is difficult to distinguish from flexibility. In the crowded environment of the cell, disorder is not compatible with the known mechanisms of proteinprotein recognition, and, foremost, with its specificity. The self-assembly of multi-component complexes may, nevertheless, involve the specific recognition of nascent polypeptide chains that are incompletely folded, but then disorder is transient, and it must remain under the control of molecular chaperones and of the quality control apparatus that obviates the toxic effects it can have on the cell.

Conserved RNA Helicase FRH Acts Nonenzymatically to Support the Intrinsically Disordered Neurospora Clock Protein FRQ

“…The debate between these two models has evidence on both sides and has given rise to a new term as an alternative to IDPs: proteins waiting for partners (PWPs) (Janin and Sternberg, 2013; Uversky and Dunker, 2013). Partners for IDPs have sometimes been termed “Nanny” proteins and the definition of a Nanny is a flexible one (Tsvetkov et al, 2009).…”

Intrinsically disordered regions of p53 family are highly diversified in evolution

“…In fact, the skepticism on the existence of IDPs in vivo is supported by the reasoning that IDPs/IDPRs cannot exist in cells except transiently since cells have elaborate mechanisms to deal with misfolded proteins (so called unfolded protein response, UPR) and these mechanisms would clear disordered proteins [134]. However, one should remember that UPR seems to be specific for eukaryotes (where it is confined to the endoplasmic reticulum (ER) [135]), and that the prokaryotic cells do not have similar mechanisms.…”

Identification of Atg3 as an intrinsically disordered polypeptide yields insights into the molecular dynamics of autophagy-related proteins in yeast

“…Many IDPs and IDPRs undergo disorder-to-order transition upon binding to a biological partner (such as a protein, nucleic acid, or a cofactor), but some retain their disorder in the biologically active state. [8][9][10][11] The conformational plasticity of IDPs and IDPRs confers unique biological properties that provide many advantages over the function of globular proteins. 10,[12][13][14] For example, this structural flexibility increases the speed of interaction and overcomes steric restrictions, which enables larger interaction surfaces.…”