Targeting Intrinsically Disordered Proteins through Dynamic Interactions

Chen, Jianlin; Liu, Xiaorong; Chen, Jianhan

doi:10.3390/biom10050743

Cited by 40 publications

(40 citation statements)

References 140 publications

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“…Specifically, the overall shape, transient secondary structures and/or long-range contacts in p53-TAD may be perturbed, which could alter the availability of key binding residues and/or change the entropic cost of binding to various regulators 56 . Such conformational modulation mechanisms have been demonstrated in previous studies of CREB/CBP 57 , Connexin43 and 4E-BP2 58-59 , as well as interaction of IDPs with several drug molecules 60-64 . Importantly, although cancer-associated mutations in p53 are predominantly located within its DBD, a large number of clinically relevant residue substitutions occur within the TAD 65 .…”

Section: Introductionsupporting

confidence: 65%

Cancer-Associated Mutations Perturb the Structure and Interactions of the Intrinsically Disordered p53 Transactivation Domain

Thevarajan

Liu

et al. 2020

Preprint

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Intrinsically disordered proteins (IDPs) are key components of regulatory networks that control crucial aspects of cell decision making. The intrinsically disordered transactivation domain (TAD) of tumor suppressor p53 mediates its interactions with multiple regulatory pathways to control the p53 homeostasis during the cellular response to genotoxic stress. Many cancer-associated mutations have been discovered in p53-TAD, but their structural and functional consequences are poorly understood. Here, by combining atomistic simulations, NMR spectroscopy, and binding assays, we demonstrate that cancer-associated mutations can significantly perturb the balance of p53 interactions with key activation and degradation regulators. Importantly, mutations do not all directly disrupt the known interaction interfaces. Instead, some mutations likely modulate the disordered state of p53-TAD, which affects the interactions. Our work suggests that the disordered conformational ensemble of p53-TAD can serve as a central conduit in regulating the response to various cellular stimuli at the protein-protein interaction level. Understanding how the disordered state of IDPs may be modulated by regulatory signals and/or disease associated perturbations will be essential in the studies on the role of IDPs in biology and diseases.

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Section: Introductionsupporting

confidence: 65%

Cancer-Associated Mutations Perturb the Structure and Interactions of the Intrinsically Disordered p53 Transactivation Domain

Thevarajan

Liu

et al. 2020

Preprint

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“…Unstructured proteins and regions can be experimentally characterized using a wide range of biophysical methods such as nuclear magnetic resonance, small-angle X-ray scattering, and mass spectrometry [ 21 ]. Advances in computational approaches have provided greater insight into the structure, dynamics, and functional roles played by disordered proteins.…”

Section: Introductionmentioning

confidence: 99%

On the Prevalence and Potential Functionality of an Intrinsic Disorder in the MERS-CoV Proteome

Alshehri

Manee

Alqahtani

et al. 2021

Viruses

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Middle East respiratory syndrome is a severe respiratory illness caused by an infectious coronavirus. This virus is associated with a high mortality rate, but there is as of yet no effective vaccine or antibody available for human immunity/treatment. Drug design relies on understanding the 3D structures of viral proteins; however, arriving at such understanding is difficult for intrinsically disordered proteins, whose disorder-dependent functions are key to the virus’s biology. Disorder is suggested to provide viral proteins with highly flexible structures and diverse functions that are utilized when invading host organisms and adjusting to new habitats. To date, the functional roles of intrinsically disordered proteins in the mechanisms of MERS-CoV pathogenesis, transmission, and treatment remain unclear. In this study, we performed structural analysis to evaluate the abundance of intrinsic disorder in the MERS-CoV proteome and in individual proteins derived from the MERS-CoV genome. Moreover, we detected disordered protein binding regions, namely, molecular recognition features and short linear motifs. Studying disordered proteins/regions in MERS-CoV could contribute to unlocking the complex riddles of viral infection, exploitation strategies, and drug development approaches in the near future by making it possible to target these important (yet challenging) unstructured regions.

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“…Small-angle X-ray scattering (SAXS) and electron microscopy (EM) gives an in-situ ensemble model describing the conformational behavior of the disordered region. Molecular dynamics (MDs) is used to refine and propose such ensembles [29][30][31].…”

Section: Introductionmentioning

confidence: 99%

Analysis of Protein Disorder Predictions in the Light of a Protein Structural Alphabet

Brevern

2020

Biomolecules

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Intrinsically-disordered protein (IDP) characterization was an amazing change of paradigm in our classical sequence-structure-function theory. Moreover, IDPs are over-represented in major disease pathways and are now often targeted using small molecules for therapeutic purposes. This has had created a complex continuum from order-that encompasses rigid and flexible regions-to disorder regions; the latter being not accessible through classical crystallographic methodologies. In X-ray structures, the notion of order is dictated by access to resolved atom positions, providing rigidity and flexibility information with low and high experimental B-factors, while disorder is associated with the missing (non-resolved) residues. Nonetheless, some rigid regions can be found in disorder regions. Using ensembles of IDPs, their local conformations were analyzed in the light of a structural alphabet. An entropy index derived from this structural alphabet allowed us to propose a continuum of states from rigidity to flexibility and finally disorder. In this study, the analysis was extended to comparing these results to disorder predictions, underlying a limited correlation, and so opening new ideas to characterize and predict disorder.

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Targeting Intrinsically Disordered Proteins through Dynamic Interactions

Cited by 40 publications

References 140 publications

Cancer-Associated Mutations Perturb the Structure and Interactions of the Intrinsically Disordered p53 Transactivation Domain

Cancer-Associated Mutations Perturb the Structure and Interactions of the Intrinsically Disordered p53 Transactivation Domain

On the Prevalence and Potential Functionality of an Intrinsic Disorder in the MERS-CoV Proteome

Analysis of Protein Disorder Predictions in the Light of a Protein Structural Alphabet

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