Intrinsically Disordered Proteins: Critical Components of the Wetware

Abstract

Despite the wealth of knowledge gained about intrinsically disordered proteins (IDPs) since their discovery, there are several aspects that remain unexplored and, hence, poorly understood. A living cell is a complex adaptive system that can be described as a wetwarea metaphor used to describe the cell as a computer comprising both hardware and software and attuned to logic gatescapable of “making” decisions. In this focused Review, we discuss how IDPs, as critical components of the wetware, influence cell-fate decisions by wiring protein interaction networks to keep them minimally frustrated. Because IDPs lie between order and chaos, we explore the possibility that they can be modeled as attractors. Further, we discuss how the conformational dynamics of IDPs manifests itself as conformational noise, which can potentially amplify transcriptional noise to stochastically switch cellular phenotypes. Finally, we explore the potential role of IDPs in prebiotic evolution, in forming proteinaceous membrane-less organelles, in the origin of multicellularity, and in protein conformation-based transgenerational inheritance of acquired characteristics. Together, these ideas provide a new conceptual framework to discern how IDPs may perform critical biological functions despite their lack of structure.

IDPConformerGenerator: A Flexible Software Suite for Sampling the Conformational Space of Disordered Protein States

“…We hope that our goal of developing a user-friendly and flexible platform will draw more researchers to the field of intrinsically disordered protein structural characterization, which in one view should be almost half the size of the folded protein structural biology community, given the relative amounts of disorder and folded structure in eukaryotic proteomes (∼0.35 to 0.65). 4 Ultimately, the resulting structural ensembles should provide physical insights into how these abundant and dynamics states regulate and carry out their critical biological functions and how disease variants in IDPs/IDRs lead to pathology.…”

“…More significantly, this platform is being developed to include back-calculators for comparison to experimental data and Bayesian scoring and reweighting approaches such as X-EISD. , We envision that IDPConformerGenerator will be the basis for an expanding platform of tools to facilitate the structural characterization of IDPs and IDRs consistent with solution experimental data. We hope that our goal of developing a user-friendly and flexible platform will draw more researchers to the field of intrinsically disordered protein structural characterization, which in one view should be almost half the size of the folded protein structural biology community, given the relative amounts of disorder and folded structure in eukaryotic proteomes (∼0.35 to 0.65) . Ultimately, the resulting structural ensembles should provide physical insights into how these abundant and dynamics states regulate and carry out their critical biological functions and how disease variants in IDPs/IDRs lead to pathology.…”

“…Disordered states of proteins, including unfolded states, intrinsically disordered regions (IDRs) of otherwise folded domains, and full intrinsically disordered proteins (IDPs), are increasingly recognized for the roles that they play in folding kinetics, aggregation propensity, , critical biological functions, and pathological disease states . Structural insights are needed to better understand these disordered protein states, and a variety of solution experiments have been developed to enable structural and dynamic descriptions of disordered proteins using nuclear magnetic resonance (NMR), small-angle X-ray scattering (SAXS), single-molecule fluorescence (SMF), and other data types. − However, solution experimental data for disordered states are averaged over a very large number of heterogeneous interconverting conformations, leading to greater challenges in structural interpretation than for folded proteins.…”

A Study on the Nature of SARS-CoV-2 Using the Shell Disorder Models: Reproducibility, Evolution, Spread, and Attenuation

“…SDMs are based on the concept of protein intrinsic disorder, which is defined as a lack of unique structure in part of the whole functional protein [ 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ]. Multiple computational tools have been developed to predict disorder.…”

IDPConformerGenerator: A Flexible Software Suite for Sampling Conformational Space of Disordered Protein States

“…Disordered states of proteins, including unfolded states, intrinsically disordered regions (IDRs) of otherwise folded domains, as well as full intrinsically disordered proteins (IDPs) are increasingly recognized for the roles they play in folding kinetics 1 aggregation propensity 2,3 , critical biological functions 4 , and pathological disease states 5 . Structural insights are needed to better understand these disordered protein states, and a variety of solution experiments have been developed to enable structural and dynamic descriptions of disordered proteins using nuclear magnetic resonance (NMR), small angle X-ray scattering (SAXS), single molecule fluorescence (SMF) and other data types [6][7][8][9][10][11] .…”