Transient exposure of a buried phosphorylation site in an autoinhibited protein

Orioli, Simone; Hansen, Carl G. Henning; Lindorff‐Larsen, Kresten

doi:10.1016/j.bpj.2021.11.2890

Cited by 10 publications

(11 citation statements)

References 65 publications

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“…It has been shown previously that phosphorylation often occurs in the disordered/flexible regions of proteins. , This is because these sites must be accessible to kinases, phosphatases, or regulatory enzymes that recognize these sites. However, some P-sites are found buried in solvent inaccessible regions of proteins as well. , To better understand how P-sites in solvent inaccessible regions are phosphorylated, we analyzed the sites in different structural contexts with specific focus on possible allosteric mechanisms like a conformational switch that exposes such sites and makes it accessible to kinase. Our results suggest that 40% of P-sites were seen in structural regions that had helical or β strand propensity and that P-sites that are in buried regions of protein structures were often surrounded by solvent exposed amino acids (Figure ), indicating that these buried sites might get exposed upon small conformational changes.…”

Section: Resultsmentioning

confidence: 99%

Panoramic Perspective on Human Phosphosites

et al. 2022

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Protein phosphorylation is the most common reversible post-translational modification of proteins and is key in the regulation of many cellular processes. Due to this importance, phosphorylation is extensively studied, resulting in the availability of a large amount of mass spectrometry-based phospho-proteomics data. Here, we leverage the information in these large-scale phospho-proteomics data sets, as contained in Scop3P, to analyze and characterize proteome-wide protein phosphorylation sites (P-sites). First, we set out to differentiate correctly observed P-sites from false-positive sites using five complementary site properties. We then describe the context of these P-sites in terms of the protein structure, solvent accessibility, structural transitions and disorder, and biophysical properties. We also investigate the relative prevalence of disease-linked mutations on and around P-sites. Moreover, we assess the structural dynamics of P-sites in their phosphorylated and unphosphorylated states. As a result, we show how large-scale reprocessing of available proteomics experiments can enable a more reliable view on proteome-wide P-sites. Furthermore, adding the structural context of proteins around P-sites helps uncover possible conformational switches upon phosphorylation. Moreover, by placing sites in different biophysical contexts, we show the differential preference in protein dynamics at phosphorylated sites when compared to the nonphosphorylated counterparts.

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Section: Resultsmentioning

confidence: 99%

Panoramic Perspective on Human Phosphosites

et al. 2022

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“…This is because these sites must be accessible to kinases, phosphatases or regulatory enzymes that recognize these sites. But some P-sites are found buried in solvent inaccessible regions of proteins as well 21,68 . To better understand how P-sites in solvent inaccessible regions are phosphorylated, we analyzed the sites in different structural context with specific focus on possible allosteric mechanisms like a conformational switch that exposes such sites and makes it accessible for kinase.…”

Section: Resultsmentioning

confidence: 99%

A panoramic perspective on human phosphosites

Ramasamy

Vandermarliere

Vranken

et al. 2022

Preprint

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Protein phosphorylation is the most common post-translational reversible modification of proteins and is key in the regulation of many cellular processes. Due to this importance, phosphorylation is extensively studied, resulting in the availability of a large amount of mass spectrometry based phospho-proteomics data. Here, we leverage the information in these large-scale phospho-proteomics datasets, as contained in Scop3P, to analyze and characterize proteome-wide protein phosphorylation sites (P-sites). First, we set out to differentiate correctly observed P-sites from false positive sites using five complementary site properties. We then describe the context of these P-sites in terms of protein structure, solvent accessibility, structural transitions and disorder, and biophysical properties. We also investigate the relative prevalence of disease-linked mutations on and around P-sites. Moreover, we also assess structural dynamics of P-sites in their phosphorylated and unphosphorylated state. Our study shows that the residues that gets phosphorylated are more flexible than their equivalent non-phosphorylated residues. Our structural and biophysical analyses of P-sites in solvent inaccessible (buried) regions of proteins show that these sites are primarily found in multi-site phospho-proteins, where highly dynamic structural transitions can occur upon binding with another protein. Finally, our analysis of the biophysical properties of P-site mutations shows that P-site mutations that occur in structurally rigid regions are more often involved in disease.

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“…In more detail, in a case in which the phosphorylatable site is not accessible to the solvent, the effect on regulation is classified as unknown in the simple mode . The ensemble mode is required to understand the possibility that a cryptic phosphorylated site is made accessible by conformational changes 50,51 . If the site has solvent accessibility of its side chain higher than 20%, the variant is expected to be damaging for the regulatory effect associated with the PTM unless it is a substitution of serine to threonine or vice versa (neutral) or substitution of tyrosine to serine/thre-onine or vice versa (unknown).…”

Section: Resultsmentioning

confidence: 99%

MAVISp: A Modular Structure-Based Framework for Protein Variant Effects

Arnaudi

Beltrame

Degn

et al. 2022

Preprint

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Cancer is a complex group of diseases due to the accumulation of mutations in tumor suppressors or oncogenes in the genome. Cancer alterations can be very heterogeneous, even in tumors from the same tissue, affecting the response to treatment and risks of relapse in different patients. The role of genomics variants on cancer predisposition, progression, and response to treatment continues to be realized. Thanks to advances in sequencing techniques and their introduction in a clinical setting, the number of genomic variants discovered is growing exponentially. Many of these variants are classified as Variants of Uncertain Significance (VUS), while other variants have been reported with conflicting evidence. Applications of bioinformatic-based approaches to characterize the effects of these variants demonstrated their full potential thanks to advances in machine learning, comparisons between predicted effects and cellular readouts, and advances in the field of structural biology and biomolecular simulations. We here introduce a modular structure-based framework for the annotations and classification of the impact of variants affecting the coding region of genes and impacting on the corresponding protein product (MAVISp, Multi-layered Assessment of VarIants by Structure for proteins) together with a Streamlit-based web application (https://github.com/ELELAB/MAVISp) where the variants and the data generated by the assessment are made available to the community for consultation or further studies. Currently, MAVISp includes information for ten different proteins and more than 4000 variants. New protein targets are routinely analyzed in batches through standardized Python-based workflows and high-throughput free energy and biomolecular simulations. We also illustrate the potential of the approach for each protein included in the database. New variants will be deposited on a regular base or in connection with future publications where the approach will be applied. Finally, we provide guidelines for new contributors who are interested in contributing to the collection in relation to their research.

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Transient exposure of a buried phosphorylation site in an autoinhibited protein

Cited by 10 publications

References 65 publications

Panoramic Perspective on Human Phosphosites

Panoramic Perspective on Human Phosphosites

A panoramic perspective on human phosphosites

MAVISp: A Modular Structure-Based Framework for Protein Variant Effects

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