Time, space, and disorder in the expanding proteome universe

Abstract

Proteins are highly dynamic entities. Their myriad functions require specific structures, but proteins’ dynamic nature ranges all the way from the local mobility of their amino acid constituents to mobility within and well beyond single cells. A truly comprehensive view of the dynamic structural proteome includes: (i) alternative sequences, (ii) alternative conformations, (iii) alternative interactions with a range of biomolecules, (iv) cellular localizations, (v) alternative behaviors in different cell types. While these aspects have traditionally been explored one protein at a time, we highlight recently emerging global approaches that accelerate comprehensive insights into these facets of the dynamic nature of protein structure. Computational tools that integrate and expand on multiple orthogonal data types promise to enable the transition from a disjointed list of static snapshots to a structurally explicit understanding of the dynamics of cellular mechanisms.

Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding

“…Most recently, many IDPs/IDRs are found to be able to undergo liquid–liquid phase separation (LLPS), which is related to the assembling of membraneless organelles in vivo . So far, studies on IDPs/IDRs have greatly extended our understanding on the sequence–structure–function relationship of proteins . Recently, the protein structure–function continuum concept was proposed by Uversky to illustrate the numerous biological functions of p53 through multiple proteoforms by various mechanisms and may be extended to many multi‐function IDPs …”

“…[45][46][47][48][49][50][51][52][53] So far, studies on IDPs/IDRs have greatly extended our understanding on the sequence-structurefunction relationship of proteins. 29,[54][55][56] Recently, the protein structure-function continuum concept was proposed by Uversky to illustrate the numerous biological functions of p53 through multiple proteoforms by various mechanisms and may be extended to many multi-function IDPs. 57 In this review, we will summarize recent advances of our understanding on the molecular recognition of IDPs/IDRs.…”

Cellular labelling favours unfolded proteins

“…Intrinsically disordered regions (IDRs) within proteins often overlap with sites of alternative splicing and post-translational modifications (PTMs). Both splicing and PTMs together are estimated to expand the number of proteoforms into the millions despite a relatively compact (~20,000 large) protein-coding human genome [5][6][7] . Proteins rich in IDRs, Intrinsically Disordered Proteins (IDPs), are often linked to diseases such as cancer, neurodegeneration and heart diseases [8][9][10][11][12][13] .…”

Sequence fingerprints distinguish erroneous from correct predictions of intrinsically disordered protein regions

“…Several protein science research groups have analyzed protein intrinsic disorder from the perspective of genomics and proteomics (Dunker et al, 2000;Linding et al, 2003;Ward et al, 2004;Radivojac et al, 2007). Since IDP regions occupy a considerable percentage of residue positions in most viral (Minde, Dunker & Lilley, 2017) and all non-viral proteomes so far investigated (Xue, Dunker & Uversky, 2012;Oates et al, 2013), it has become important to analyze the sequences of these proteins with a variety of computational approaches to uncover the conserved structural and functional features of these proteins Saravanan & Selvaraj, 2017).…”