scholarly journals Rebuilding Ring-Type Assembly of Peroxiredoxin by Chemical Modification

2020 ◽  
Author(s):  
Tomoki Himiyama ◽  
Yuko Tsuchiya ◽  
Yasushige Yonezawa ◽  
Tsutomu Nakamura
Keyword(s):  
Amino Acid ◽  
Protein Interactions ◽  
Hot Spots ◽  
Quaternary Structure ◽  
Protein Assembly ◽  
Protein Protein Interactions ◽  
Aeropyrum Pernix ◽  
Amino Acid Mutations ◽  
Regulate Protein ◽  
Additional Amino Acid

Direct control of protein quaternary structure (QS) is challenging owing to the complexity of protein structure. As a protein with a characteristic QS, peroxiredoxin from <i>Aeropyrum pernix</i> K1 (ApPrx) forms a decamer, wherein five dimers associate to form a ring. Here, we disrupted and reconstituted ApPrx QS via amino acid mutations and chemical modifications targeting hot spots for protein assembly. The decameric QS of an ApPrx* mutant, wherein all cysteine residues in wild-type ApPrx were mutated to serine, was destructed to dimers via an F80C mutation. The dimeric ApPrx*F80C mutant was then modified with a small molecule and successfully assembled as a decamer. Structural analysis confirmed that an artificially installed chemical moiety potentially facilitates suitable protein-protein interactions to rebuild a native structure. Rebuilding of dodecamer was also achieved through an additional amino acid mutation. This study describes a facile method to regulate protein assembly state.

scholarly journals Rebuilding Ring-Type Assembly of Peroxiredoxin by Chemical Modification

2020 ◽  
Author(s):  
Tomoki Himiyama ◽  
Yuko Tsuchiya ◽  
Yasushige Yonezawa ◽  
Tsutomu Nakamura
Keyword(s):  
Amino Acid ◽  
Protein Interactions ◽  
Hot Spots ◽  
Quaternary Structure ◽  
Protein Assembly ◽  
Protein Protein Interactions ◽  
Aeropyrum Pernix ◽  
Amino Acid Mutations ◽  
Regulate Protein ◽  
Additional Amino Acid

Direct control of protein quaternary structure (QS) is challenging owing to the complexity of protein structure. As a protein with a characteristic QS, peroxiredoxin from <i>Aeropyrum pernix</i> K1 (ApPrx) forms a decamer, wherein five dimers associate to form a ring. Here, we disrupted and reconstituted ApPrx QS via amino acid mutations and chemical modifications targeting hot spots for protein assembly. The decameric QS of an ApPrx* mutant, wherein all cysteine residues in wild-type ApPrx were mutated to serine, was destructed to dimers via an F80C mutation. The dimeric ApPrx*F80C mutant was then modified with a small molecule and successfully assembled as a decamer. Structural analysis confirmed that an artificially installed chemical moiety potentially facilitates suitable protein-protein interactions to rebuild a native structure. Rebuilding of dodecamer was also achieved through an additional amino acid mutation. This study describes a facile method to regulate protein assembly state.

Influence of Amino Acid Mutations and Small Molecules on Targeted Inhibition of Proteins Involved in Cancer

2019 ◽  
Vol 19 (6) ◽  
pp. 457-466 ◽  
Author(s):  
V. Kanakaveti ◽  
P. Anoosha ◽  
R. Sakthivel ◽  
S.K. Rayala ◽  
M.M. Gromiha
Keyword(s):  
Amino Acid ◽  
Small Molecules ◽  
Protein Interactions ◽  
Chemical Space ◽  
Clinical Success ◽  
Growth Factor Receptor ◽  
Protein Protein Interactions ◽  
Functional Aspects ◽  
Amino Acid Mutations ◽  
Targeted Inhibition

Background:Protein-protein interactions (PPIs) are of crucial importance in regulating the biological processes of cells both in normal and diseased conditions. Significant progress has been made in targeting PPIs using small molecules and achieved promising results. However, PPI drug discovery should be further accelerated with better understanding of chemical space along with various functional aspects.Objective:In this review, we focus on the advancements in computational research for targeted inhibition of protein-protein interactions involved in cancer.Methods:Here, we mainly focused on two aspects: (i) understanding the key roles of amino acid mutations in epidermal growth factor receptor (EGFR) as well as mutation-specific inhibitors and (ii) design of small molecule inhibitors for Bcl-2 to disrupt PPIs.Results:The paradigm of PPI inhibition to date reflect the certainty that inclination towards novel and versatile strategies enormously dictate the success of PPI inhibition. As the chemical space highly differs from the normal drug like compounds the lead optimization process has to be given the utmost priority to ensure the clinical success. Here, we provided a broader perspective on effect of mutations in oncogene EGFR connected to Bcl-2 PPIs and focused on the potential challenges.Conclusion:Understanding and bridging mutations and altered PPIs will provide insights into the alarming signals leading to massive malfunctioning of a biological system in various diseases. Finding rational elucidations from a pharmaceutical stand point will presumably broaden the horizons in future.

scholarly journals SAAMBE-3D: Predicting Effect of Mutations on Protein–Protein Interactions

2020 ◽  
Vol 21 (7) ◽  
pp. 2563 ◽  
Author(s):  
Swagata Pahari ◽  
Gen Li ◽  
Adithya Krishna Murthy ◽  
Siqi Liang ◽  
Robert Fragoza ◽  
...  
Keyword(s):  
Amino Acid ◽  
Protein Interactions ◽  
Binding Free Energy ◽  
Pearson Correlation ◽  
Normal Function ◽  
Protein Protein Interactions ◽  
Cornell University ◽  
Genome Wide ◽  
New Development ◽  
Amino Acid Mutations

Maintaining wild type protein–protein interactions is essential for the normal function of cell and any mutation that alter their characteristics can cause disease. Therefore, the ability to correctly and quickly predict the effect of amino acid mutations is crucial for understanding disease effects and to be able to carry out genome-wide studies. Here, we report a new development of the SAAMBE method, SAAMBE-3D, which is a machine learning-based approach, resulting in accurate predictions and is extremely fast. It achieves the Pearson correlation coefficient ranging from 0.78 to 0.82 depending on the training protocol in benchmarking five-fold validation test against the SKEMPI v2.0 database and outperforms currently existing algorithms on various blind-tests. Furthermore, optimized and tested via five-fold cross-validation on the Cornell University dataset, the SAAMBE-3D achieves AUC of 1.0 and 0.96 on a homo and hereto-dimer test datasets. Another important feature of SAAMBE-3D is that it is very fast, it takes less than a fraction of a second to complete a prediction. SAAMBE-3D is available as a web server and as well as a stand-alone code, the last one being another important feature allowing other researchers to directly download the code and run it on their local computer. Combined all together, SAAMBE-3D is an accurate and fast software applicable for genome-wide studies to assess the effect of amino acid mutations on protein–protein interactions. The webserver and the stand-alone codes (SAAMBE-3D for predicting the change of binding free energy and SAAMBE-3D-DN for predicting if the mutation is disruptive or non-disruptive) are available.

A structural view of the dissociation ofEscherichia colitryptophanase

2015 ◽  
Vol 71 (12) ◽  
pp. 2364-2371
Author(s):  
Keren Green ◽  
Nasrin Qasim ◽  
Garik Gdaelvsky ◽  
Anna Kogan ◽  
Yehuda Goldgur ◽  
...  
Keyword(s):  
Amino Acid ◽  
Protein Interactions ◽  
Quaternary Structure ◽  
Hydrophobic Interactions ◽  
Molecular Axis ◽  
Amino Acid Residues ◽  
Protein Protein Interactions ◽  
E Coli ◽  
Reversible Loss ◽  
Structure Of Proteins

Tryptophanase (Trpase) is a pyridoxal 5′-phosphate (PLP)-dependent homotetrameric enzyme which catalyzes the degradation of L-tryptophan. Trpase is also known for its cold lability, which is a reversible loss of activity at low temperature (2°C) that is associated with the dissociation of the tetramer.Escherichia coliTrpase dissociates into dimers, whileProteus vulgarisTrpase dissociates into monomers. As such, this enzyme is an appropriate model to study the protein–protein interactions and quaternary structure of proteins. The aim of the present study was to understand the differences in the mode of dissociation between theE. coliandP. vulgarisTrpases. In particular, the effect of mutations along the molecular axes of homotetrameric Trpase on its dissociation was studied. To answer this question, two groups of mutants of theE. colienzyme were created to resemble the amino-acid sequence ofP. vulgarisTrpase. In one group, residues 15 and 59 that are located along the molecular axisR(also termed the noncatalytic axis) were mutated. The second group included a mutation at position 298, located along the molecular axisQ(also termed the catalytic axis). Replacing amino-acid residues along theRaxis resulted in dissociation of the tetramers into monomers, similar to theP. vulgarisTrpase, while replacing amino-acid residues along theQaxis resulted in dissociation into dimers only. The crystal structure of the V59M mutant ofE. coliTrpase was also determined in its apo form and was found to be similar to that of the wild type. This study suggests that inE. coliTrpase hydrophobic interactions along theRaxis hold the two monomers together more strongly, preventing the dissociation of the dimers into monomers. Mutation of position 298 along theQaxis to a charged residue resulted in tetramers that are less susceptible to dissociation. Thus, the results indicate that dissociation ofE. coliTrpase into dimers occurs along the molecularQaxis.

scholarly journals Androgen signaling uses a writer and a reader of ADP-ribosylation to regulate protein complex assembly

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chun-Song Yang ◽  
Kasey Jividen ◽  
Teddy Kamata ◽  
Natalia Dworak ◽  
Luke Oostdyk ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Interactions ◽  
Prostate Cancer Cells ◽  
Protein Protein Interactions ◽  
Post Translational Modification ◽  
Complex Assembly ◽  
Adp Ribosylation ◽  
Signaling Axis ◽  
Regulate Protein ◽  
Protein Complex Assembly

AbstractAndrogen signaling through the androgen receptor (AR) directs gene expression in both normal and prostate cancer cells. Androgen regulates multiple aspects of the AR life cycle, including its localization and post-translational modification, but understanding how modifications are read and integrated with AR activity has been difficult. Here, we show that ADP-ribosylation regulates AR through a nuclear pathway mediated by Parp7. We show that Parp7 mono-ADP-ribosylates agonist-bound AR, and that ADP-ribosyl-cysteines within the N-terminal domain mediate recruitment of the E3 ligase Dtx3L/Parp9. Molecular recognition of ADP-ribosyl-cysteine is provided by tandem macrodomains in Parp9, and Dtx3L/Parp9 modulates expression of a subset of AR-regulated genes. Parp7, ADP-ribosylation of AR, and AR-Dtx3L/Parp9 complex assembly are inhibited by Olaparib, a compound used clinically to inhibit poly-ADP-ribosyltransferases Parp1/2. Our study reveals the components of an androgen signaling axis that uses a writer and reader of ADP-ribosylation to regulate protein-protein interactions and AR activity.

scholarly journals The Role of Posttranslational Modifications in DNA Repair

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Miaomiao Bai ◽  
Dongdong Ti ◽  
Qian Mei ◽  
Jiejie Liu ◽  
Xin Yan ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Protein Interactions ◽  
Posttranslational Modifications ◽  
Genome Stability ◽  
Protein Localization ◽  
Complex Structure ◽  
Protein Protein Interactions ◽  
Regulate Protein

The human body is a complex structure of cells, which are exposed to many types of stress. Cells must utilize various mechanisms to protect their DNA from damage caused by metabolic and external sources to maintain genomic integrity and homeostasis and to prevent the development of cancer. DNA damage inevitably occurs regardless of physiological or abnormal conditions. In response to DNA damage, signaling pathways are activated to repair the damaged DNA or to induce cell apoptosis. During the process, posttranslational modifications (PTMs) can be used to modulate enzymatic activities and regulate protein stability, protein localization, and protein-protein interactions. Thus, PTMs in DNA repair should be studied. In this review, we will focus on the current understanding of the phosphorylation, poly(ADP-ribosyl)ation, ubiquitination, SUMOylation, acetylation, and methylation of six typical PTMs and summarize PTMs of the key proteins in DNA repair, providing important insight into the role of PTMs in the maintenance of genome stability and contributing to reveal new and selective therapeutic approaches to target cancers.

Engineering an acetyllysine reader with photocrosslinking amino acid for interactome profiling

2021 ◽  
Author(s):  
Babu Sudhamalla ◽  
Anirban Roy ◽  
Soumen Barman ◽  
Jyotirmayee Padhan
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Protein Interactions ◽  
Unnatural Amino Acids ◽  
Protein Protein Interactions ◽  
Site Specific ◽  
Powerful Approach

The site-specific installation of light-activable crosslinker unnatural amino acids offers a powerful approach to trap transient protein-protein interactions both in vitro and in vivo. Herein, we engineer a bromodomain to...

scholarly journals Engineering bromodomains with a photoactive amino acid by engaging ‘Privileged’ tRNA synthetases

2020 ◽  
Vol 56 (25) ◽  
pp. 3641-3644
Author(s):  
Shana Wagner ◽  
Babu Sudhamalla ◽  
Philip Mannes ◽  
Sushma Sappa ◽  
Sam Kavoosi ◽  
...  
Keyword(s):  
Amino Acid ◽  
Chemical Synthesis ◽  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Site Specific ◽  
Trna Synthetases

An improved chemical synthesis, site-specific incorporation and enhanced photo-crosslinking ability of tmdF have been demonstrated in the context of protein–protein interactions.

Sign in / Sign up

Export Citation Format

Share Document