Functional Anthology of Intrinsic Disorder. 2. Cellular Components, Domains, Technical Terms, Developmental Processes, and Coding Sequence Diversities Correlated with Long Disordered Regions

Abstract

Biologically active proteins without stable ordered structure (i.e., intrinsically disordered proteins) are attracting increased attention. Functional repertoires of ordered and disordered proteins are very different, and the ability to differentiate whether a given function is associated with intrinsic disorder or with a well-folded protein is crucial for modern protein science. However, there is a large gap between the number of proteins experimentally confirmed to be disordered and their actual number in nature. As a result, studies of functional properties of confirmed disordered proteins, while helpful in revealing the functional diversity of protein disorder, provide only a limited view. To overcome this problem, a bioinformatics approach for comprehensive study of functional roles of protein disorder was proposed in the first paper of this series (Xie H., Vucetic S., Iakoucheva L.M., Oldfield C.J., Dunker A.K., Obradovic Z., Uversky V.N. (2006) Functional anthology of intrinsic disorder. I. Biological processes and functions of proteins with long disordered regions. J. Proteome Res.). Applying this novel approach to Swiss-Prot sequences and functional keywords, we found over 238 and 302 keywords to be strongly positively or negatively correlated, respectively, with long intrinsically disordered regions. This paper describes ~90 Swiss-Prot keywords attributed to the cellular components, domains, technical terms, developmental processes and coding sequence diversities possessing strong positive and negative correlation with long disordered regions.

Exceptionally abundant exceptions: comprehensive characterization of intrinsic disorder in all domains of life

“…Many IDRs contain specific identification regions, which they use to participate in various regulation, recognition, signaling and control pathways [11,12]. As exemplified by the gene ontology analysis, IDPs are involved in crucial biological processes, such as signaling, recognition, and regulation [14,15,[18][19][20][21].…”

“…Many IDRs contain specific identification regions, which they use to participate in various regulation, recognition, signaling and control pathways [11,12]. As exemplified by the gene ontology analysis, IDPs are involved in crucial biological processes, such as signaling, recognition, and regulation [14,15,[18][19][20][21].The existence of functional proteins without unique 3D-structures is in apparent conflict with the traditional sequence-structure-function paradigm that relies on the "one protein-one structure-one function" concept [1,2,5,6,11,12,15,22]. For a long time, cases of protein function without structure or protein function originating from the conformational ensemble were taken as unique and rare exceptions, and the one protein-one structure-one function concept was considered as a general and undisputable rule.…”

“…Based on the bioinformatics analysis of the functional keywords associated with 20 or more proteins in Swiss-Prot, it was concluded that many functions are indeed related to the increased propensity for intrinsic disorder. Specifically, out of 710 Swiss-Prot keywords, 310 functional keywords are associated with ordered proteins, 238 functional keywords are attributed to disordered proteins, and the remainder 162 keywords yield ambiguity in the likely function-structure associations [19][20][21]. Study of the occurrence of protein disorder in the human proteome and analysis of the ontology categories that are enriched in disordered human proteins revealed that the IDP-specific functions are both length and position dependent, and these observations were used to develop classifiers for human protein function prediction [32].…”

Exploring the binding diversity of intrinsically disordered proteins involved in one‐to‐many binding

“…[26][27][28][29][30][31][32][33] Many of these disorder-utilizing biological functions depend ultimately on disorderbased PPIs. Thus, understanding the structural basis of PPIs involving IDPs is important for a wide variety of biological functions, not just as the mechanistic basis for hub protein function.…”

The Basics of Protein Sequence Analysis

“…For recent reviews on structure-function relationships of fibrous and intrinsically disordered proteins (IDPs) proteins the reader should consult ref. 18 and refs [19][20][21] , respectively. Bioinformatics methodology for prediction of regions of disorder is reviewed in detail in the chapter by Majorek et al in this volume.…”