Research Article: Intrinsically disordered proteins and structured proteins with intrinsically disordered regions have different functional roles in the cell

Date Published: August 19, 2019

Publisher: Public Library of Science

Author(s): Antonio Deiana, Sergio Forcelloni, Alessandro Porrello, Andrea Giansanti, Eugene A. Permyakov.


Many studies about classification and the functional annotation of intrinsically disordered proteins (IDPs) are based on either the occurrence of long disordered regions or the fraction of disordered residues in the sequence. Taking into account both criteria we separate the human proteome, taken as a case study, into three variants of proteins: i) ordered proteins (ORDPs), ii) structured proteins with intrinsically disordered regions (IDPRs), and iii) intrinsically disordered proteins (IDPs). The focus of this work is on the different functional roles of IDPs and IDPRs, which up until now have been generally considered as a whole. Previous studies assigned a large set of functional roles to the general category of IDPs. We show here that IDPs and IDPRs have non-overlapping functional spectra, play different roles in human diseases, and deserve to be treated as distinct categories of proteins. IDPs enrich only a few classes, functions, and processes: nucleic acid binding proteins, chromatin binding proteins, transcription factors, and developmental processes. In contrast, IDPRs are spread over several functional protein classes and GO annotations which they partly share with ORDPs. As regards to diseases, we observe that IDPs enrich only cancer-related proteins, at variance with previous results reporting that IDPs are widespread also in cardiovascular and neurodegenerative pathologies. Overall, the operational separation of IDPRs from IDPs is relevant towards correct estimates of the occurrence of intrinsically disordered proteins in genome-wide studies and in the understanding of the functional spectra associated to different flavors of protein disorder.

Partial Text

Over the last two decades, the concept of ‘intrinsic disorder’ has emerged as a prominent and influential topic in protein science [1–7]. The discovery of intrinsically disordered proteins (IDPs), i.e., functional proteins lacking a well-defined tertiary structure, has challenged the traditional sequence-structure-function paradigm [8,9]. In their seminal paper, Uversky, Gillespie, and Fink [2] introduced the “charge-hydrophobicity phase space”, which clarified that IDPs are characterized by a combination of “low overall hydrophobicity and large net charge”. IDPs constitute, in eukaryotes, a substantial part of the cellular proteome and are involved in many biological processes that complement the functional repertoires of ordered proteins [10,11]. Ever-increasing experimental evidence has revealed the presence of disordered regions also in well-structured proteins [12,13]. Then the distinction between intrinsically disordered proteins, i.e., proteins lacking a tertiary structure, and structured proteins containing intrinsically disordered regions gradually emerged [14–17]. An operational distinction of these two variants is the main objective of the present work. A note on terminology is in order at this point. The editors of the journal Intrinsically Disordered Proteins made an effort to disambiguate the semantics of protein intrinsic disorder [18]. They proposed “intrinsically disordered proteins” as a unifying term, recognizing that it is a compromise “far from being ideal”, and suggesting that “additional descriptors” would emerge, apt to clarify the many aspects of “structurelessness” that are included in one term. The terminology we adopt here is surely also not ideal. Let us try to make clear that we use here IDPs, when referring to previous studies, as the general unifying term proposed by Dunker et al. We use IDPs also to denote a subgroup of Dunker et al.’s IDPs, a variant that is operationally specified here as distinct from the variant of mostly structured proteins with long intrinsically disordered regions (we call here IDPRs).

In this study we operationally distinguish the functional spectra and biological roles of three broad variants of intrinsic protein disorder: i) ordered proteins (ORDPs), ii) structured proteins with intrinsically disordered protein regions (IDPRs), and iii) intrinsically disordered proteins (IDPs). The focus of this work is on the functional distinction and the different roles in diseases of IDPs and IDPRs, as we distinguish them.




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