scholarly journals Templated folding of intrinsically disordered proteins

2020 ◽  
Vol 295 (19) ◽  
pp. 6586-6593 ◽  
Author(s):  
Angelo Toto ◽  
Francesca Malagrinò ◽  
Lorenzo Visconti ◽  
Francesca Troilo ◽  
Livia Pagano ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Current Knowledge ◽  
Large Fraction ◽  
Globular Proteins ◽  
Order Transition ◽  
Disordered Proteins ◽  
Linear Free Energy Relationship ◽  
Intrinsically Disordered ◽  
Linear Free Energy ◽  
Induced Folding

Much of our current knowledge of biological chemistry is founded in the structure-function relationship, whereby sequence determines structure that determines function. Thus, the discovery that a large fraction of the proteome is intrinsically disordered, while being functional, has revolutionized our understanding of proteins and raised new and interesting questions. Many intrinsically disordered proteins (IDPs) have been determined to undergo a disorder-to-order transition when recognizing their physiological partners, suggesting that their mechanisms of folding are intrinsically different from those observed in globular proteins. However, IDPs also follow some of the classic paradigms established for globular proteins, pointing to important similarities in their behavior. In this review, we compare and contrast the folding mechanisms of globular proteins with the emerging features of binding-induced folding of intrinsically disordered proteins. Specifically, whereas disorder-to-order transitions of intrinsically disordered proteins appear to follow rules of globular protein folding, such as the cooperative nature of the reaction, their folding pathways are remarkably more malleable, due to the heterogeneous nature of their folding nuclei, as probed by analysis of linear free-energy relationship plots. These insights have led to a new model for the disorder-to-order transition in IDPs termed “templated folding,” whereby the binding partner dictates distinct structural transitions en route to product, while ensuring a cooperative folding.

scholarly journals Understanding the Binding Induced Folding of Intrinsically Disordered Proteins by Protein Engineering: Caveats and Pitfalls

2020 ◽  
Vol 21 (10) ◽  
pp. 3484 ◽  
Author(s):  
Francesca Malagrinò ◽  
Lorenzo Visconti ◽  
Livia Pagano ◽  
Angelo Toto ◽  
Francesca Troilo ◽  
...  
Keyword(s):  
Free Energy ◽  
Intrinsically Disordered Proteins ◽  
Three Dimensional ◽  
Globular Proteins ◽  
Disordered Proteins ◽  
Dimensional Structure ◽  
Value Analysis ◽  
Intrinsically Disordered ◽  
Induced Folding ◽  
Key Techniques

Many proteins lack a well-defined three-dimensional structure in isolation. These proteins, typically denoted as intrinsically disordered proteins (IDPs), may display a characteristic disorder-to-order transition when binding their physiological partner(s). From an experimental perspective, it is of great importance to establish the general grounds to understand how such folding processes may be explored. Here we discuss the caveats and the pitfalls arising when applying to IDPs one of the key techniques to characterize the folding of globular proteins, the Φ value analysis. This method is based on measurements of the free energy changes of transition and native states upon conservative, non-disrupting, mutations. On the basis of available data, we reinforce the validity of Φ value analysis in the study of IDPs and suggest future experiments to further validate this powerful experimental method.

scholarly journals Sequence Versus Composition: What Prescribes IDP Biophysical Properties?

Entropy ◽  
2019 ◽  
Vol 21 (7) ◽  
pp. 654 ◽  
Author(s):  
Jiří Vymětal ◽  
Jiří Vondrášek ◽  
Klára Hlouchová
Keyword(s):  
Amino Acid ◽  
Secondary Structure ◽  
Intrinsically Disordered Proteins ◽  
Random Sequence ◽  
Bioinformatic Analysis ◽  
Globular Proteins ◽  
Disordered Proteins ◽  
Compositional Bias ◽  
Intrinsically Disordered ◽  
Sequence Versus

Intrinsically disordered proteins (IDPs) represent a distinct class of proteins and are distinguished from globular proteins by conformational plasticity, high evolvability and a broad functional repertoire. Some of their properties are reminiscent of early proteins, but their abundance in eukaryotes, functional properties and compositional bias suggest that IDPs appeared at later evolutionary stages. The spectrum of IDP properties and their determinants are still not well defined. This study compares rudimentary physicochemical properties of IDPs and globular proteins using bioinformatic analysis on the level of their native sequences and random sequence permutations, addressing the contributions of composition versus sequence as determinants of the properties. IDPs have, on average, lower predicted secondary structure contents and aggregation propensities and biased amino acid compositions. However, our study shows that IDPs exhibit a broad range of these properties. Induced fold IDPs exhibit very similar compositions and secondary structure/aggregation propensities to globular proteins, and can be distinguished from unfoldable IDPs based on analysis of these sequence properties. While amino acid composition seems to be a major determinant of aggregation and secondary structure propensities, sequence randomization does not result in dramatic changes to these properties, but for both IDPs and globular proteins seems to fine-tune the tradeoff between folding and aggregation.

scholarly journals Intrinsically Disordered Proteins in Chronic Diseases

Biomolecules ◽  
2019 ◽  
Vol 9 (4) ◽  
pp. 147 ◽  
Author(s):  
Prakash Kulkarni ◽  
Vladimir Uversky
Keyword(s):  
Chronic Diseases ◽  
Intrinsically Disordered Proteins ◽  
Large Fraction ◽  
3D Structure ◽  
Human Proteome ◽  
Disordered Proteins ◽  
3D Structures ◽  
Physiological Conditions ◽  
Intrinsically Disordered

It is now increasingly evident that a large fraction of the human proteome comprises proteins that, under physiological conditions, lack fixed, ordered 3D structures as a whole or have segments that are not likely to form a defined 3D structure [...]

scholarly journals Hierarchical Ensembles of Intrinsically Disordered Proteins at Atomic Resolution in Molecular Dynamics Simulations

2019 ◽  
Author(s):  
Lisa M. Pietrek ◽  
Lukas S. Stelzl ◽  
Gerhard Hummer
Keyword(s):  
Molecular Dynamics ◽  
Local Structure ◽  
High Performance ◽  
Intrinsically Disordered Proteins ◽  
Large Fraction ◽  
Conformational Dynamics ◽  
Full Length ◽  
Atomic Resolution ◽  
Disordered Proteins ◽  
Intrinsically Disordered

AbstractIntrinsically disordered proteins (IDPs) constitute a large fraction of the human proteome and are critical in the regulation of cellular processes. A detailed understanding of the conformational dynamics of IDPs could help to elucidate their roles in health and disease. However the inherent flexibility of IDPs makes structural studies and their interpretation challenging. Molecular dynamics (MD) simulations could address this challenge in principle, but inaccuracies in the simulation models and the need for long simulations have stymied progress. To overcome these limitations, we adopt an hierarchical approach that builds on the “flexible meccano” model of Bernadó et al. (J. Am. Chem. Soc. 2005, 127, 17968-17969). First, we exhaustively sample small IDP fragments in all-atom simulations to capture local structure. Then, we assemble the fragments into full-length IDPs to explore the stereochemically possible global structures of IDPs. The resulting ensembles of three-dimensional structures of full-length IDPs are highly diverse, much more so than in standard MD simulation. For the paradigmatic IDP α-synuclein, our ensemble captures both local structure, as probed by nuclear magnetic resonance (NMR) spectroscopy, and its overall dimension, as obtained from small-angle X-ray scattering (SAXS) in solution. By generating representative and meaningful starting ensembles, we can begin to exploit the massive parallelism afforded by current and future high-performance computing resources for atomic-resolution characterization of IDPs.

scholarly journals Cyclic Ion Mobility – Collision Activation Experiments Elucidate Protein Behaviour in the Gas-Phase

2020 ◽  
Author(s):  
Charles Eldrid ◽  
Jakub Ujma ◽  
Hannah Britt ◽  
Tristan Cragnolini ◽  
Symeon Kalfas ◽  
...  
Keyword(s):  
Gas Phase ◽  
Ion Mobility ◽  
Protein Unfolding ◽  
Intrinsically Disordered Proteins ◽  
Conformational Dynamics ◽  
Globular Proteins ◽  
Disordered Proteins ◽  
Mass Selection ◽  
Intrinsically Disordered ◽  
Partially Folded States

<i>Elucidating the properties of intrinsically disordered proteins (IDPs) and unfolded and partially folded states of globular proteins is challenging owing to their heterogeneous and dynamic nature. Protein unfolding and misfolding is a key feature of a broad range of debilitating diseases, whilst the conformational propensities of intrinsically disordered proteins can play a significant role in modulating their activity, and the properties of unfolded states of globular proteins modulates their stability and tendency to aggregate. Ion mobility-mass spectrometry (IM-MS) is a powerful method for interrogating these systems, however limits in resolution and the difficulty in probing the energetics of interconversions amongst heterogeneous ensembles are major issues. Herein, using a quadrupole/cyclic-IM/ time-of-flight MS instrument, we show how the combination of precursor mass selection, mobility selection (IM<sup>n</sup>) and collisional activation (CA) allows the elucidation of complicated gas-phase dynamic behavior. The methodology employed is general and is demonstrated using a classic model globular protein, cytochrome C, and an aggregation-prone IDP, amylin. CA allows investigations of protein conformational dynamics and unfolding in the gas-phase for heterogeneous mixtures, whilst the additional precursor mass selection capability provides high resolution and selectivity, facilitating more in-depth investigation. Understanding protein dynamics in the gas-phase will allow greater insight into protein behaviour and allow application of gas-phase techniques to clinically relevant systems. </i>

scholarly journals Phosphorylation-induced conformational dynamics in an intrinsically disordered protein and potential role in phenotypic heterogeneity

2017 ◽  
Vol 114 (13) ◽  
pp. E2644-E2653 ◽  
Author(s):  
Prakash Kulkarni ◽  
Mohit Kumar Jolly ◽  
Dongya Jia ◽  
Steven M. Mooney ◽  
Ajay Bhargava ◽  
...  
Keyword(s):  
Single Molecule ◽  
Intrinsically Disordered Proteins ◽  
Large Fraction ◽  
Conformational Dynamics ◽  
3D Structure ◽  
Random Coil ◽  
Disordered Proteins ◽  
Conformational Ensemble ◽  
Intrinsically Disordered ◽  
Androgen Independent

Intrinsically disordered proteins (IDPs) that lack a unique 3D structure and comprise a large fraction of the human proteome play important roles in numerous cellular functions. Prostate-Associated Gene 4 (PAGE4) is an IDP that acts as a potentiator of the Activator Protein-1 (AP-1) transcription factor. Homeodomain-Interacting Protein Kinase 1 (HIPK1) phosphorylates PAGE4 at S9 and T51, but only T51 is critical for its activity. Here, we identify a second kinase, CDC-Like Kinase 2 (CLK2), which acts on PAGE4 and hyperphosphorylates it at multiple S/T residues, including S9 and T51. We demonstrate that HIPK1 is expressed in both androgen-dependent and androgen-independent prostate cancer (PCa) cells, whereas CLK2 and PAGE4 are expressed only in androgen-dependent cells. Cell-based studies indicate that PAGE4 interaction with the two kinases leads to opposing functions. HIPK1-phosphorylated PAGE4 (HIPK1-PAGE4) potentiates c-Jun, whereas CLK2-phosphorylated PAGE4 (CLK2-PAGE4) attenuates c-Jun activity. Consistent with the cellular data, biophysical measurements (small-angle X-ray scattering, single-molecule fluorescence resonance energy transfer, and NMR) indicate that HIPK1-PAGE4 exhibits a relatively compact conformational ensemble that binds AP-1, whereas CLK2-PAGE4 is more expanded and resembles a random coil with diminished affinity for AP-1. Taken together, the results suggest that the phosphorylation-induced conformational dynamics of PAGE4 may play a role in modulating changes between PCa cell phenotypes. A mathematical model based on our experimental data demonstrates how differential phosphorylation of PAGE4 can lead to transitions between androgen-dependent and androgen-independent phenotypes by altering the AP-1/androgen receptor regulatory circuit in PCa cells.

scholarly journals Differential dehydration effects on globular proteins and intrinsically disordered proteins during film formation

2017 ◽  
Vol 26 (4) ◽  
pp. 718-726 ◽  
Author(s):  
Juliana Sakamoto Yoneda ◽  
Andew J. Miles ◽  
Ana Paula Ulian Araujo ◽  
B. A. Wallace
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Film Formation ◽  
Globular Proteins ◽  
Disordered Proteins ◽  
Intrinsically Disordered

Intrinsically disordered proteins: administration not executive

2012 ◽  
Vol 40 (5) ◽  
pp. 945-949 ◽  
Author(s):  
Mike P. Williamson ◽  
Jennifer R. Potts
Keyword(s):  
Executive Functions ◽  
Intrinsically Disordered Proteins ◽  
Globular Proteins ◽  
Disordered Proteins ◽  
Pharmaceutical Intervention ◽  
Intrinsically Disordered ◽  
Good Target ◽  
Eukaryotic Genomes

IDPs (intrinsically disordered proteins) are common in eukaryotic genomes and have regulatory roles. In the cell, they are disordered, although not completely random. They bind weakly, but specifically, often remaining partially disordered even when bound. Whereas folded globular proteins have ‘executive’ roles in the cell, IDPs have an essential administrative function, making sure that the executive functions are properly co-ordinated. This makes them a good target for pharmaceutical intervention.

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