scholarly journals Hidden dynamic signatures drive substrate selectivity in the disordered phosphoproteome

2020 ◽  
Vol 117 (38) ◽  
pp. 23606-23616
Author(s):  
Min-Hyung Cho ◽  
James O. Wrabl ◽  
James Taylor ◽  
Vincent J. Hilser
Keyword(s):  
Conformational Equilibrium ◽  
Energy Difference ◽  
Statistical Thermodynamic ◽  
Sequence Information ◽  
Substrate Selectivity ◽  
Phosphorylation Sites ◽  
Information Encoding ◽  
Conformational Ensembles ◽  
Protein Substrates ◽  
Conservation Patterns

Phosphorylation sites are hyperabundant in the eukaryotic disordered proteome, suggesting that conformational fluctuations play a major role in determining to what extent a kinase interacts with a particular substrate. In biophysical terms, substrate selectivity may be determined not just by the structural–chemical complementarity between the kinase and its protein substrates but also by the free energy difference between the conformational ensembles that are, or are not, recognized by the kinase. To test this hypothesis, we developed a statistical-thermodynamics-based informatics framework, which allows us to probe for the contribution of equilibrium fluctuations to phosphorylation, as evaluated by the ability to predict Ser/Thr/Tyr phosphorylation sites in the disordered proteome. Essential to this framework is a decomposition of substrate sequence information into two types: vertical information encoding conserved kinase specificity motifs and horizontal information encoding substrate conformational equilibrium that is embedded, but often not apparent, within position-specific conservation patterns. We find not only that conformational fluctuations play a major role but also that they are the dominant contribution to substrate selectivity. In fact, the main substrate classifier distinguishing selectivity is the magnitude of change in local compaction of the disordered chain upon phosphorylation of these mostly singly phosphorylated sites. In addition to providing fundamental insights into the consequences of phosphorylation across the proteome, our approach provides a statistical-thermodynamic strategy for partitioning any sequence-based search into contributions from structural–chemical complementarity and those from changes in conformational equilibrium.

scholarly journals Hidden dynamic signatures drive substrate selectivity in the disordered phosphoproteome

2019 ◽  
Author(s):  
Min-Hyung Cho ◽  
James O. Wrabl ◽  
James Taylor ◽  
Vincent J. Hilser
Keyword(s):  
High Performance ◽  
Conformational Dynamics ◽  
Phosphorylation Site ◽  
Energy Difference ◽  
Disordered Proteins ◽  
Statistical Thermodynamic ◽  
Sequence Information ◽  
Substrate Selectivity ◽  
Phosphorylation Sites ◽  
Information Encoding

AbstractPhosphorylation sites are hyper-abundant in the disordered proteins of eukaryotes, suggesting that conformational dynamics (or heterogeneity) may play a major role in determining to what extent a kinase interacts with a particular substrate. In biophysical terms, substrate selectivity may be determined not just by the structural and chemical complementarity between the kinase and its protein substrates, but also by the free energy difference between the conformational ensembles that are recognized by the kinase and those that are not. To test this hypothesis, we developed an informatics framework based on statistical thermodynamics, which allows us to probe for dynamic contributions to phosphorylation, as evaluated by the ability to predict Ser/Thr/ Tyr phosphorylation sites in the disordered proteome. Essential to this framework is a decomposition of substrate sequence information into two types: vertical information encoding conserved kinase specificity motifs and horizontal (distributed) information encoding substrate conformational dynamics that are embedded, but often not apparent, within position specific conservation patterns. We find not only that conformational dynamics play a major role, but that they are the dominant contribution to substrate selectivity. In fact, the main substrate classifier distinguishing selectivity is the magnitude of change in compaction of the disordered chain upon phosphorylation. Thus, in addition to providing fundamental insights into the underlying mechanistic consequences of phosphorylation across the entire proteome, our approach provides a novel statistical thermodynamic strategy for partitioning any sequence-based search into contributions from direct chemical and structural complementarity and those from changes in conformational dynamics. Using this framework, we developed a high-performance open-source phosphorylation site predictor, PHOSforUS, which is freely available at https://github.com/bxlab/PHOSforUS.

An I.R. Spectroscopic Study of the Conformational Equilibrium in 2-Acetylfuran

1976 ◽  
Vol 31 (10) ◽  
pp. 1217-1219 ◽  
Author(s):  
Giulio Paliani ◽  
Rosario Cataliotti ◽  
Antonio Poletti
Keyword(s):  
Dielectric Constant ◽  
Spectroscopic Study ◽  
Equilibrium Position ◽  
Conformational Equilibrium ◽  
Energy Difference ◽  
Temperature Changes

Abstract The conformational cis/trans equilibrium of 2-Acetylfuran has been studied by i.r. spectroscopy, in various physical states. This equilibrium is strongly influenced by the dielectric constant of the medium. The isomeric energy difference is very small as revealed by the insensitivity of the equilibrium position to temperature changes.

scholarly journals treeWidget: a BioJS component to visualise phylogenetic trees

F1000Research ◽  
2014 ◽  
Vol 3 ◽  
pp. 49 ◽  
Author(s):  
Fabian Schreiber
Keyword(s):  
Phylogenetic Trees ◽  
Protein Domains ◽  
Gene Families ◽  
Sequence Information ◽  
Gene Duplications ◽  
Link Type ◽  
History Of ◽  
Conservation Patterns ◽  
Evolution Of Gene Families ◽  
The Web

Summary: Phylogenetic trees are widely used to represent the evolution of gene families. As the history of gene families can be complex (including lots of gene duplications), its visualisation can become a difficult task. A good/accurate visualisation of phylogenetic trees - especially on the web - allows easier understanding and interpretation of trees to help to reveal the mechanisms that shape the evolution of a specific set of gene/species. Here, I present treeWidget, a modular BioJS component to visualise phylogenetic trees on the web. Through its modularity, treeWidget can be easily customized to allow the display of sequence information, e.g. protein domains and alignment conservation patterns.Availability: http://github.com/biojs/biojs; http://dx.doi.org/10.5281/zenodo.7707

scholarly journals Individual PKC-Phosphorylation Sites in Organic Cation Transporter 1 Determine Substrate Selectivity and Transport Regulation

2005 ◽  
Vol 16 (6) ◽  
pp. 1562-1570 ◽  
Author(s):  
Giuliano Ciarimboli ◽  
Hermann Koepsell ◽  
Mariya Iordanova ◽  
Valentin Gorboulev ◽  
Brigitte Dürner ◽  
...  
Keyword(s):  
Organic Cation ◽  
Organic Cation Transporter ◽  
Substrate Selectivity ◽  
Phosphorylation Sites ◽  
Transport Regulation ◽  
Organic Cation Transporter 1

scholarly journals Conserved SQ and QS motifs in bacterial effectors suggest pathogen interplay with the ATM kinase family during infection

2018 ◽  
Author(s):  
Davide Sampietro ◽  
Hugo Sámano-Sánchez ◽  
Norman E. Davey ◽  
Malvika Sharan ◽  
Bálint Mészáros ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Effector Proteins ◽  
Phosphorylation Sites ◽  
Dna Breaks ◽  
Atm Kinase ◽  
Protein Substrates ◽  
Kinase Family ◽  
Atm Signaling Pathway ◽  
Bacterial Effectors ◽  
Atm Signaling

AbstractUnderstanding how bacteria hijack eukaryotic cells during infection is vital to develop better strategies to counter the pathologies that they cause. ATM kinase family members phosphorylate eukaryotic protein substrates on Ser or Thr residues followed by Gln. The kinases are active under oxidative stress conditions and/or the presence of ds-DNA breaks. While examining the protein sequences of well-known bacterial effector proteins such as CagA and Tir, we noticed that they often show conserved (S/TQ) motifs, even though the evidence for effector phosphorylation by ATM has not been reported. We undertook a bioinformatics analysis to examine effectors for their potential to mimic the eukaryotic substrates of the ATM kinase. The candidates we found could interfere with the host’s intracellular signaling network upon interaction, which might give an advantage to the pathogen inside the host. Further, the putative phosphorylation sites should be accessible, conserved across species and, in the vicinity to the phosphorylation sites, positively charged residues should be depleted. We also noticed that the reverse motif (QT/S) is often also conserved and located close to (S/TQ) sites, indicating its potential biological role in ATM kinase function. Our findings could suggest a mechanism of infection whereby many pathogens inactivate/modulate the host ATM signaling pathway.

scholarly journals HRCM: An Efficient Hybrid Referential Compression Method for Genomic Big Data

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Haichang Yao ◽  
Yimu Ji ◽  
Kui Li ◽  
Shangdong Liu ◽  
Jing He ◽  
...  
Keyword(s):  
Genomic Data ◽  
Sequence Information ◽  
Memory Consumption ◽  
Compression Method ◽  
Genome Sequences ◽  
Information Encoding ◽  
Transmission Cost ◽  
Information Matching ◽  
Three Stages ◽  
Single Sequence

With the maturity of genome sequencing technology, huge amounts of sequence reads as well as assembled genomes are generating. With the explosive growth of genomic data, the storage and transmission of genomic data are facing enormous challenges. FASTA, as one of the main storage formats for genome sequences, is widely used in the Gene Bank because it eases sequence analysis and gene research and is easy to be read. Many compression methods for FASTA genome sequences have been proposed, but they still have room for improvement. For example, the compression ratio and speed are not so high and robust enough, and memory consumption is not ideal, etc. Therefore, it is of great significance to improve the efficiency, robustness, and practicability of genomic data compression to reduce the storage and transmission cost of genomic data further and promote the research and development of genomic technology. In this manuscript, a hybrid referential compression method (HRCM) for FASTA genome sequences is proposed. HRCM is a lossless compression method able to compress single sequence as well as large collections of sequences. It is implemented through three stages: sequence information extraction, sequence information matching, and sequence information encoding. A large number of experiments fully evaluated the performance of HRCM. Experimental verification shows that HRCM is superior to the best-known methods in genome batch compression. Moreover, HRCM memory consumption is relatively low and can be deployed on standard PCs.

DeepPPSite: A deep learning-based model for analysis and prediction of phosphorylation sites using efficient sequence information

2021 ◽  
Vol 612 ◽  
pp. 113955
Author(s):  
Saeed Ahmed ◽  
Muhammad Kabir ◽  
Muhammad Arif ◽  
Zaheer Ullah Khan ◽  
Dong-Jun Yu
Keyword(s):  
Deep Learning ◽  
Sequence Information ◽  
Phosphorylation Sites ◽  
Efficient Sequence

scholarly journals The Crystal Structures of Substrate and Nucleotide Complexes of Enterococcus faecium Aminoglycoside-2′′-Phosphotransferase-IIa [APH(2′′)-IIa] Provide Insights into Substrate Selectivity in the APH(2′′) Subfamily

2009 ◽  
Vol 191 (13) ◽  
pp. 4133-4143 ◽  
Author(s):  
Paul G. Young ◽  
Rupa Walanj ◽  
Vendula Lakshmi ◽  
Laura J. Byrnes ◽  
Peter Metcalf ◽  
...  
Keyword(s):  
Bacterial Resistance ◽  
Gram Negative Bacteria ◽  
Substrate Selectivity ◽  
Phosphorylation Sites ◽  
Molecular Replacement ◽  
Aminoglycoside Phosphotransferases ◽  
Binding Cleft ◽  
Starting Model ◽  
Aspartate Residue ◽  
Structural Insights

ABSTRACT Aminoglycoside-2′′-phosphotransferase-IIa [APH(2′′)-IIa] is one of a number of homologous bacterial enzymes responsible for the deactivation of the aminoglycoside family of antibiotics and is thus a major component in bacterial resistance to these compounds. APH(2′′)-IIa produces resistance to several clinically important aminoglycosides (including kanamycin and gentamicin) in both gram-positive and gram-negative bacteria, most notably in Enterococcus species. We have determined the structures of two complexes of APH(2′′)-IIa, the binary gentamicin complex and a ternary complex containing adenosine-5′-(β,γ-methylene)triphosphate (AMPPCP) and streptomycin. This is the first crystal structure of a member of the APH(2′′) family of aminoglycoside phosphotransferases. The structure of the gentamicin-APH(2′′)-IIa complex was solved by multiwavelength anomalous diffraction methods from a single selenomethionine-substituted crystal and was refined to a crystallographic R factor of 0.210 (R free, 0.271) at a resolution of 2.5 Å. The structure of the AMPPCP-streptomycin complex was solved by molecular replacement using the gentamicin-APH(2′′)-IIa complex as the starting model. The enzyme has a two-domain structure with the substrate binding site located in a cleft in the C-terminal domain. Gentamicin binding is facilitated by a number of conserved acidic residues lining the binding cleft, with the A and B rings of the substrate forming the majority of the interactions. The inhibitor streptomycin, although binding in the same pocket as gentamicin, is orientated such that no potential phosphorylation sites are adjacent to the catalytic aspartate residue. The binding of gentamicin and streptomycin provides structural insights into the substrate selectivity of the APH(2′′) subfamily of aminoglycoside phosphotransferases, specifically, the selectivity between the 4,6-disubstituted and the 4,5-disubstituted aminoglycosides.

scholarly journals Dual domain recognition determines SARS-CoV-2 PLpro selectivity for human ISG15 and K48-linked di-ubiquitin

2021 ◽  
Author(s):  
Jerzy Osipiuk ◽  
Pawel M Wydorski ◽  
Benjamin T Lanham ◽  
Christine Tesar ◽  
Michael Endres ◽  
...  
Keyword(s):  
Active Phase ◽  
Solution Nmr ◽  
Substrate Selectivity ◽  
Functional Protein ◽  
Protein Substrates ◽  
The World ◽  
Energetic Analysis ◽  
Interferon Stimulated Gene 15 ◽  
Dual Domain ◽  
Binding Interfaces

The Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) genome is evolving as the viral pandemic continues its active phase around the world. The Papain-like protease (PLpro) is a domain of Nsp3 – a large multi-domain protein that is an essential component of the replication-transcription complex, making it a good therapeutic target. PLpro is a multi-functional protein encoded in coronaviruses that can cleave viral polyproteins, poly-ubiquitin and protective Interferon Stimulated Gene 15 product, ISG15, which mimics a head-to-tail linked ubiquitin (Ub) dimer. PLpro across coronavirus families showed divergent selectivity for recognition and cleavage of these protein substrates despite sequence conservation. However, it is not clear how sequence changes in SARS-CoV-2 PLpro alter its selectivity for substrates and what outcome this has on the pathogenesis of the virus. We show that SARS-CoV-2 PLpro preferentially binds ISG15 over Ub and K48-linked Ub2. We determined crystal structures of PLpro in complex with human K48-Ub2 and ISG15 revealing that dual domain recognition of ISG15 drives substrate selectivity over Ub and Ub2. We also characterized the PLpro substrate interactions using solution NMR, cross-linking mass spectrometry to support that ISG15 is recognized via two domains while Ub2 binds primarily through one Ub domain. Finally, energetic analysis of the binding interfaces between PLpro from SARS-CoV-1 and SARS-CoV-2 with ISG15 and Ub2 define the sequence determinants for how PLpros from different coronaviruses recognize two topologically distinct substrates and how evolution of the protease altered its substrate selectivity. Our work reveals how PLpro substrate selectivity may evolve in PLpro coronaviruses variants enabling design of more effective therapeutics.

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