scholarly journals Sequence effects on size, shape, and structural heterogeneity in Intrinsically Disordered Proteins

2018 ◽  
Author(s):  
Upayan Baul ◽  
Debayan Chakraborty ◽  
Mauro L. Mugnai ◽  
John E. Straub ◽  
D. Thirumalai
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Scaling Law ◽  
Three Dimensional ◽  
Structural Heterogeneity ◽  
Structural Features ◽  
Coarse Grained ◽  
Disordered Proteins ◽  
Cellular Functions ◽  
Intrinsically Disordered ◽  
Sequence Effects

AbstractIntrinsically disordered proteins (IDPs) lack well-defined three-dimensional structures, thus challenging the archetypal notion of structure-function relationships. Determining the ensemble of conformations that IDPs explore under physiological conditions is the first step towards understanding their diverse cellular functions. Here, we quantitatively characterize the structural features of IDPs as a function of sequence and length using coarse-grained simulations. For diverse IDP sequences, with the number of residues (NT) ranging from 24 to 441, our simulations not only reproduce the radii of gyration (Rg) obtained from experiments, but also predict the full scattering intensity profiles in very good agreement with Small Angle X-ray Scattering experiments. The Rg values are well-described by the standard Flory scaling law, , with v ≈ 0.588, making it tempting to assert that IDPs behave as polymers in a good solvent. However, clustering analysis reveals that the menagerie of structures explored by IDPs is diverse, with the extent of heterogeneity being highly sequence-dependent, even though ensemble-averaged properties, such as the dependence of Rg on chain length, may suggest synthetic polymer-like behavior in a good solvent. For example, we show that for the highly charged Prothymosin-α, a substantial fraction of conformations is highly compact. Even if the sequence compositions are similar, as is the case for α-Synuclein and a truncated construct from the Tau protein, there are substantial differences in the conformational heterogeneity. Taken together, these observations imply that metrics based on net charge or related quantities alone, cannot be used to anticipate the phases of IDPs, either in isolation or in complex with partner IDPs or RNA. Our work sets the stage for probing the interactions of IDPs with each other, with folded protein domains, or with partner RNAs, which are critical for describing the structures of stress granules and biomolecular condensates with important cellular functions.Graphical TOC Entry

Structural characterization of intrinsically disordered proteins by the combined use of NMR and SAXS

2012 ◽  
Vol 40 (5) ◽  
pp. 955-962 ◽  
Author(s):  
Nathalie Sibille ◽  
Pau Bernadó
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Dynamic Models ◽  
Dimensional Space ◽  
Three Dimensional ◽  
Main Tool ◽  
Structural Features ◽  
Disordered Proteins ◽  
Dimensional Structure ◽  
Intrinsically Disordered ◽  
Conformational Preferences

In recent years, IDPs (intrinsically disordered proteins) have emerged as pivotal actors in biology. Despite IDPs being present in all kingdoms of life, they are more abundant in eukaryotes where they are involved in the vast majority of regulation and signalling processes. The realization that, in some cases, functional states of proteins were partly or fully disordered was in contradiction to the traditional view where a well defined three-dimensional structure was required for activity. Several experimental evidences indicate, however, that structural features in IDPs such as transient secondary-structural elements and overall dimensions are crucial to their function. NMR has been the main tool to study IDP structure by probing conformational preferences at residue level. Additionally, SAXS (small-angle X-ray scattering) has the capacity to report on the three-dimensional space sampled by disordered states and therefore complements the local information provided by NMR. The present review describes how the synergy between NMR and SAXS can be exploited to obtain more detailed structural and dynamic models of IDPs in solution. These combined strategies, embedded into computational approaches, promise the elucidation of the structure–function properties of this important, but elusive, family of biomolecules.

Disorder-function relationships for the cell cycle regulatory proteins p21 and p27

2012 ◽  
Vol 393 (4) ◽  
pp. 259-274 ◽  
Author(s):  
Diana M. Mitrea ◽  
Mi-Kyung Yoon ◽  
Li Ou ◽  
Richard W. Kriwacki
Keyword(s):  
Cell Division ◽  
Molecular Mechanisms ◽  
Intrinsically Disordered Proteins ◽  
Tertiary Structure ◽  
Structural Features ◽  
Disordered Proteins ◽  
Cellular Functions ◽  
Intrinsically Disordered ◽  
Induced Folding ◽  
Cell Cycle Regulatory Proteins

Abstract The classic structure-function paradigm has been challenged by a recently identified class of proteins: intrinsically disordered proteins (IDPs). Despite their lack of stable secondary or tertiary structure, IDPs are prevalent in all forms of life and perform myriad cellular functions, including signaling and regulation. Importantly, disruption of IDP homeostasis is associated with numerous human diseases, including cancer and neurodegeneration. Despite wide recognition of IDPs, the molecular mechanisms underlying their functions are not fully understood. Here we review the structural features and disorder-function relationships for p21 and p27, two cyclin-dependent kinase (Cdk) regulators involved in controlling cell division and fate. Studies of p21 bound to Cdk2/cyclin A revealed that a helix stretching mechanism mediates binding promiscuity. Further, investigations of Tyr88-phosphorylated p27 identified a signaling conduit that controls cell division and is disrupted in certain cancers. These mechanisms rely upon a balance between nascent structure in the free state, induced folding upon binding, and persistent flexibility within functional complexes. Although these disorder-function relationships are likely to be recapitulated in other IDPs, it is also likely that the vocabulary of their mechanisms is much more extensive than is currently understood. Further study of the physical properties of IDPs and elucidation of their links with function are needed to fully understand the mechanistic language of IDPs.

scholarly journals Sequence Effects on Size, Shape, and Structural Heterogeneity in Intrinsically Disordered Proteins

2019 ◽  
Vol 123 (16) ◽  
pp. 3462-3474 ◽  
Author(s):  
Upayan Baul ◽  
Debayan Chakraborty ◽  
Mauro L. Mugnai ◽  
John E. Straub ◽  
D. Thirumalai
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Structural Heterogeneity ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Sequence Effects

scholarly journals Disorder in a two-domain neuronal Ca2+-binding protein regulates domain stability and dynamics using ligand mimicry

2020 ◽  
Author(s):  
Lasse Staby ◽  
Katherine R. Kemplen ◽  
Amelie Stein ◽  
Michael Ploug ◽  
Jane Clarke ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Three Dimensional ◽  
Life Time ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Order And Disorder ◽  
C Terminus ◽  
Close Relationship ◽  
Stability Dynamics ◽  
And Function

Abstract Understanding the interplay between sequence, structure and function of proteins has been complicated in recent years by the discovery of intrinsically disordered proteins (IDPs), which perform biological functions in the absence of a well-defined three-dimensional fold. Disordered protein sequences account for roughly 30% of the human proteome and in many proteins, disordered and ordered domains coexist. However, few studies have assessed how either feature affects the properties of the other. In this study, we examine the role of a disordered tail in the overall properties of the two-domain, calcium-sensing protein neuronal calcium sensor 1 (NCS-1). We show that loss of just six of the 190 residues at the flexible C-terminus is sufficient to severely affect stability, dynamics, and folding behavior of both ordered domains. We identify specific hydrophobic contacts mediated by the disordered tail that may be responsible for stabilizing the distal N-terminal domain. Moreover, sequence analyses indicate the presence of an LSL-motif in the tail that acts as a mimic of native ligands critical to the observed order–disorder communication. Removing the disordered tail leads to a shorter life-time of the ligand-bound complex likely originating from the observed destabilization. This close relationship between order and disorder may have important implications for how investigations into mixed systems are designed and opens up a novel avenue of drug targeting exploiting this type of behavior.

Molecular simulations of protein disorderThis paper is one of a selection of papers published in this special issue entitled “Canadian Society of Biochemistry, Molecular & Cellular Biology 52nd Annual Meeting — Protein Folding: Principles and Diseases” and has undergone the Journal's usual peer review process.

2010 ◽  
Vol 88 (2) ◽  
pp. 269-290 ◽  
Author(s):  
Sarah Rauscher ◽  
Régis Pomès
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Peer Review Process ◽  
Structural Heterogeneity ◽  
Disordered Proteins ◽  
Cellular Biology ◽  
Protein Disorder ◽  
Conformational Ensembles ◽  
Intrinsically Disordered ◽  
Simulation Techniques ◽  
Selection Of

Protein disorder is abundant in proteomes throughout all kingdoms of life and serves many biologically important roles. Disordered states of proteins are challenging to study experimentally due to their structural heterogeneity and tendency to aggregate. Computer simulations, which are not impeded by these properties, have recently emerged as a useful tool to characterize the conformational ensembles of intrinsically disordered proteins. In this review, we provide a survey of computational studies of protein disorder with an emphasis on the interdisciplinary nature of these studies. The application of simulation techniques to the study of disordered states is described in the context of experimental and bioinformatics approaches. Experimental data can be incorporated into simulations, and simulations can provide predictions for experiment. In this way, simulations have been integrated into the existing methodologies for the study of disordered state ensembles. We provide recent examples of simulations of disordered states from the literature and our own work. Throughout the review, we emphasize important predictions and biophysical understanding made possible through the use of simulations. This review is intended as both an overview and a guide for structural biologists and theoretical biophysicists seeking accurate, atomic-level descriptions of disordered state ensembles.

scholarly journals Transient Secondary Structures as General Target-Binding Motifs in Intrinsically Disordered Proteins

2018 ◽  
Vol 19 (11) ◽  
pp. 3614 ◽  
Author(s):  
Do-Hyoung Kim ◽  
Kyou-Hoon Han
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Three Dimensional ◽  
Secondary Structures ◽  
Disordered Proteins ◽  
Ample Evidence ◽  
Binding Motifs ◽  
Intrinsically Disordered ◽  
Long Time ◽  
Science Community ◽  
Target Binding

Intrinsically disordered proteins (IDPs) are unorthodox proteins that do not form three-dimensional structures under non-denaturing conditions, but perform important biological functions. In addition, IDPs are associated with many critical diseases including cancers, neurodegenerative diseases, and viral diseases. Due to the generic name of “unstructured” proteins used for IDPs in the early days, the notion that IDPs would be completely unstructured down to the level of secondary structures has prevailed for a long time. During the last two decades, ample evidence has been accumulated showing that IDPs in their target-free state are pre-populated with transient secondary structures critical for target binding. Nevertheless, such a message did not seem to have reached with sufficient clarity to the IDP or protein science community largely because similar but different expressions were used to denote the fundamentally same phenomenon of presence of such transient secondary structures, which is not surprising for a quickly evolving field. Here, we summarize the critical roles that these transient secondary structures play for diverse functions of IDPs by describing how various expressions referring to transient secondary structures have been used in different contexts.

scholarly journals Identifying sequence perturbations to an intrinsically disordered protein that determine its phase-separation behavior

2020 ◽  
Vol 117 (21) ◽  
pp. 11421-11431 ◽  
Author(s):  
Benjamin S. Schuster ◽  
Gregory L. Dignon ◽  
Wai Shing Tang ◽  
Fleurie M. Kelley ◽  
Aishwarya Kanchi Ranganath ◽  
...  
Keyword(s):  
Phase Separation ◽  
Intrinsically Disordered Proteins ◽  
Lipid Membrane ◽  
Coarse Grained ◽  
Disordered Proteins ◽  
Sequence Features ◽  
Intrinsically Disordered ◽  
Arginine Residues

Phase separation of intrinsically disordered proteins (IDPs) commonly underlies the formation of membraneless organelles, which compartmentalize molecules intracellularly in the absence of a lipid membrane. Identifying the protein sequence features responsible for IDP phase separation is critical for understanding physiological roles and pathological consequences of biomolecular condensation, as well as for harnessing phase separation for applications in bioinspired materials design. To expand our knowledge of sequence determinants of IDP phase separation, we characterized variants of the intrinsically disordered RGG domain from LAF-1, a model protein involved in phase separation and a key component of P granules. Based on a predictive coarse-grained IDP model, we identified a region of the RGG domain that has high contact probability and is highly conserved between species; deletion of this region significantly disrupts phase separation in vitro and in vivo. We determined the effects of charge patterning on phase behavior through sequence shuffling. We designed sequences with significantly increased phase separation propensity by shuffling the wild-type sequence, which contains well-mixed charged residues, to increase charge segregation. This result indicates the natural sequence is under negative selection to moderate this mode of interaction. We measured the contributions of tyrosine and arginine residues to phase separation experimentally through mutagenesis studies and computationally through direct interrogation of different modes of interaction using all-atom simulations. Finally, we show that despite these sequence perturbations, the RGG-derived condensates remain liquid-like. Together, these studies advance our fundamental understanding of key biophysical principles and sequence features important to phase separation.

scholarly journals Expanding the proteome: disordered and alternatively folded proteins

2011 ◽  
Vol 44 (4) ◽  
pp. 467-518 ◽  
Author(s):  
H. Jane Dyson
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Significant Proportion ◽  
Experimental Studies ◽  
Three Dimensional ◽  
Protein Sequences ◽  
Open Reading Frames ◽  
Disordered Proteins ◽  
Characteristic Functions ◽  
Intrinsically Disordered ◽  
Folded Proteins

AbstractProteins provide much of the scaffolding for life, as well as undertaking a variety of essential catalytic reactions. These characteristic functions have led us to presuppose that proteins are in general functional only when well structured and correctly folded. As we begin to explore the repertoire of possible protein sequences inherent in the human and other genomes, two stark facts that belie this supposition become clear: firstly, the number of apparent open reading frames in the human genome is significantly smaller than appears to be necessary to code for all of the diverse proteins in higher organisms, and secondly that a significant proportion of the protein sequences that would be coded by the genome would not be expected to form stable three-dimensional (3D) structures. Clearly the genome must include coding for a multitude of alternative forms of proteins, some of which may be partly or fully disordered or incompletely structured in their functional states. At the same time as this likelihood was recognized, experimental studies also began to uncover examples of important protein molecules and domains that were incompletely structured or completely disordered in solution, yet remained perfectly functional. In the ensuing years, we have seen an explosion of experimental and genome-annotation studies that have mapped the extent of the intrinsic disorder phenomenon and explored the possible biological rationales for its widespread occurrence. Answers to the question ‘why would a particular domain need to be unstructured?’ are as varied as the systems where such domains are found. This review provides a survey of recent new directions in this field, and includes an evaluation of the role not only of intrinsically disordered proteins but also of partially structured and highly dynamic members of the disorder–order continuum.

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