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Post translational modification

Mahmood Haj-Yahya, Hilal A Lashuel
The microtubule-associated protein Tau plays a central role in neurodegeneration and is a leading therapeutic target for the treatment of Alzheimer's disease (AD). Several lines of evidence suggest that post-translational modifications (PTMs) regulate the function(s) of Tau, including its subcellular localization, clearance, aggregation, toxicity, and pathology spreading. However, the lack of tools and methodologies that allow site-specific introduction of PTMs in Tau have limited our ability to dissect the role of PTMs in regulating Tau functions in health and disease...
April 23, 2018: Journal of the American Chemical Society
Lei Wei, Jesse G Meyer, Birgit Schilling
Post-translational modification (PTM) of protein lysine residues by NƐ-acylation induces structural changes that can dynamically regulate protein functions, for example, by changing enzymatic activity or by mediating interactions. Precise quantification of site-specific protein acylation occupancy, or stoichiometry, is essential for understanding the functional consequences of both global low-level stoichiometry and individual high-level acylation stoichiometry of specific lysine residues. Other groups have reported measurement of lysine acetylation stoichiometry by comparing the ratio of peptide precursor isotopes from endogenous, natural abundance acylation and exogenous, heavy isotope-labeled acylation introduced after quantitative chemical acetylation of proteins using stable isotope-labeled acetic anhydride...
April 4, 2018: Journal of Visualized Experiments: JoVE
Lunxi Liang, Huanbin Wang, Hubing Shi, Zhaoli Li, Han Yao, Zhigao Bu, Ningning Song, Chushu Li, Dabin Xiang, Yao Zhang, Jilin Wang, Ye Hu, Qi Xu, Yanlei Ma, Zhongyi Cheng, Yingchao Wang, Shuliang Zhao, Jin Qian, Yingxuan Chen, Jing-Yuan Fang, Jie Xu
Many cancer-related proteins are controlled by composite post-translational modifications (PTMs), but prevalent strategies only target one type of modification. Here we describe a designed peptide that controls two types of modifications of the p53 tumor suppressor, based on the discovery of a protein complex that suppresses p53 (suppresome). We found that Morn3, a cancer-testis antigen, recruits different PTM enzymes, such as sirtuin deacetylase and ubiquitin ligase, to confer composite modifications on p53...
April 10, 2018: Cell Chemical Biology
Ching-Yu Lin, Jau-Jiuan Sheu, I-Shih Tsai, Sen-Te Wang, Li-Yu Yang, I-Uen Hsu, Hui-Wen Chang, Horng-Mo Lee, Shu-Huei Kao, Ching-Kuo Lee, Chien-Ho Chen, Yung-Feng Lin
OBJECTIVE: Advanced glycation end products (AGEs) are involved in the pathogenesis of Alzheimer's disease (AD). Specific AGEs and related autoantibodies may be early AD markers. Apolipoprotein A1 (ApoA1) and its post-translational modifications (PTMs) are associated with neurodegeneration and thus selected to test the hypothesis. METHODS: Serum samples from totally 64 AD or health control (HC) Taiwanese were analyzed. ApoA1 was isolated from the serum and examined through LC-MS/MS and PTM analyses...
April 19, 2018: Clinical Biochemistry
Young Min Kim, Eun Jung Park, Hye Jung Kim, Ki Churl Chang
Excessive inflammation plays a detrimental role in endotoxemia. A recent study indicated that alarmins such as high mobility group box 1 (HMGB1) have drawn attention as therapeutic targets of sepsis. Post-translational modification (i.e., acetylation of lysine residues) of HMGB1 leads to the release of HMGB1 into the cellular space, operating as a warning signal that induces inflammation. Sirtuin 1 (SIRT1) has been shown to negatively regulate HMGB1 hyperacetylation and its extracellular release in sepsis. Therefore, we hypothesized that the S-nitrosylation (SNO) of SIRT1 may disrupt the ability of SIRT1 to negatively regulate the hyperacetylation of HMGB1...
April 19, 2018: Biochemical and Biophysical Research Communications
Kyung Chan Park, Sharleen V Menezes, Danuta S Kalinowski, Sumit Sahni, Patric J Jansson, Zaklina Kovacevic, Des R Richardson
The metastasis suppressor, N-myc downstream regulated gene-1 (NDRG1), exhibits pleiotropic activity, inhibiting metastasis of various tumor-types, while being correlated with metastasis in others. Notably, NDRG1 phosphorylation and cleavage are associated with its function, although it is unclear if these modifications occur universally, or selectively, in different cancer cell-types and if it contributes to its pleiotropy. Considering the suggested DNA repair role of nuclear NDRG1, the effects of the above post-translational modifications on its nuclear localization was examined...
April 18, 2018: Biochimica et Biophysica Acta
Jingjing Cao, Qian Wang, Tao Liu, Nan Peng, Li Huang
Nucleic acid-binding proteins of the Sac10b family, also referred to as Alba (for acetylation lowers binding affinity), are highly conserved in Archaea. It was reported that Sso10b, a Sac10b homologue from Sulfolobus solfataricus, was acetylated at the ε-amino group of K16 and the α-amino group of the N-terminal residue. Notably, acetylation of K16 reduced the affinity of Sso10b for DNA and de-repressed transcription in vitro. Here we show that Sis10b, a Sac10b homologue from Sulfolobus islandicus, underwent a range of post-translational modifications (PTMs)...
April 21, 2018: Molecular Microbiology
Katrin Rietscher, René Keil, Annemarie Jordan, Mechthild Hatzfeld
Desmosomes are essential for strong intercellular adhesion and are abundant in tissues exposed to mechanical strain. At the same time, desmosomes need to be dynamic to allow for remodeling of epithelia during differentiation or wound healing. Phosphorylation of desmosomal plaque proteins appears essential for desmosome dynamics. However, the mechanisms how context-dependent post-translational modifications regulate desmosome formation, dynamics or stability are incompletely understood. Here, we show that growth factor signaling regulates the phosphorylation-dependent association of plakophilins 1 and 3 with 14-3-3 protein isoforms and uncover unique and partially antagonistic functions of members of the 14-3-3 family in the regulation of desmosomes...
April 20, 2018: Journal of Cell Science
Milton Roy, Dhanendra Tomar, Kritarth Singh, Sripada Lakshmi, Paresh Prajapati, Khyati Bhatelia, Dhruv Gohel, Rajesh Singh
In cancer patients, treatment modalities like chemotherapy and radiation exert their anticancer effects by inducing DNA damage. The cancer cells can survive under genotoxic stress by inducing DNA damage response (DDR) or can undergo cell death. The process of autophagy is emerging as crucial regulator of cell survival during different stress conditions. Post translational modification through ubiquitin plays an essential role in DDR during genotoxic stress conditions. Ubiquitin ligases regulate autophagy and cell death pathways however their role during genotoxic stress conditions is not understood...
April 17, 2018: Cellular Signalling
Fatemeh Torkashvand, Fereidoun Mahboudi, Manouchehr Vossoughi, Elnaz Fatemi, Seyed Masoud Moosavi Basri, Amir Heydari, Behrouz Vaziri
Background: Chinese hamster ovary (CHO) cell line is considered as the most common cell line in the biopharmaceutical industry because of its capability in performing efficient post-translational modifications and producing the recombinant proteins, which are similar to natural human proteins. The optimization of the upstream process via different feed strategies has a great impact on the target molecule expression and yield. Methods: To determine and understand the molecular events beneath the feed effects on the CHO cell, a label-free quantitative proteomic analysis was applied...
April 21, 2018: Iranian Biomedical Journal
Takumi Takata, Tooru Nakamura-Hirota, Rintaro Inoue, Ken Morishima, Nobuhiro Sato, Masaaki Sugiyama, Noriko Fujii
Senile cataract onset is caused by insolubilization of lens proteins. The lens crystallin protein family correctly orders the formation of homo- or hetero-oligomers in lens fiber cells. Because lens fiber cells do not divide, covalent post-translational modifications such as isomerization of aspartate residues, accumulate with aging. Although many isomerization sites of αA-crystallin have been reported, their structural and functional contributions have never been identified. In this study, αA-crystallin was extracted from the aged human lens and separated into each oligomeric state by size exclusion chromatography and electrophoresis...
April 20, 2018: FEBS Journal
Andrew P Fontenot
Metal-induced hypersensitivity is driven by T-cell sensitization to metal ions. Although numerous metals are associated with the development of diffuse parenchymal lung disease, beryllium-induced hypersensitivity is the best-studied to date. This review focuses on the interaction between innate and adaptive immunity that leads to the development of chronic beryllium disease. After beryllium exposure, activation of the innate immune system occurs through the engagement of pattern-recognition receptors. This activation leads to cell death, release of alarmins, and activation and migration of dendritic cells to lung-draining lymph nodes...
April 2018: Annals of the American Thoracic Society
Francesco Fiorentino, Antonello Mai, Dante Rotili
Lysine acetylation is a post-translational modification of both histone and nonhistone proteins that is catalyzed by lysine acetyltransferases and plays a key role in numerous biological contexts. The dysregulation of this enzyme activity is implicated in many human pathologies such as cancer, neurological and inflammatory disorders. Many lysine acetyltransferase inhibitors (KATi) have been developed so far, but there is still the need for new, more potent, metabolically stable and selective KATi as chemical tools for studying KAT biology and/or as potential therapeutic agents...
April 20, 2018: Future Medicinal Chemistry
Cristina Núñez, María Del Pilar Chantada, Susana B Bravo, Sergio Vázquez Estévez
Low abundance proteins/peptides usually suffer strong interference with highly abundant proteins/peptides as well as other contaminants, resulting in low ionization efficiency in MS analysis. Hence, the enrichment and separation of proteins/peptides from complex mixtures are of great value to their successful identification. In this review we present an overview of the application of different nanocomposites for the specific enrichment of peptides/proteins with post-translational modifications (PTMs), such as phosphorylation and glycosylation...
April 16, 2018: Journal of Proteomics
Yufei Liu, Chang Wang, Ran Wang, Yike Wu, Liang Zhang, Bi-Feng Liu, Liming Cheng, Xin Liu
Glycosylation is one of the most important post-translational modifications of protein. Recently, global profiling of human serum glycomics has become a noninvasive method for cancer-related biomarker discovery and many studies have focused on compositional glycan profiling. In contrast, structure-specific glycan profiling may provide more potential biomarkers with higher specificity than compositional profiling. In this work, N-glycans released from human serum were neutralized with methylamine and reduced by ammonia-borane complex prior to profiling using nanoLC-ESI-MS with porous graphitized carbon (PGC) and relative abundances of over 280 isomers were compared between pancreatic cancer (PC) cases (n = 32) and healthy controls (n = 32)...
April 16, 2018: Journal of Proteomics
Evan W McConnell, Emily G Werth, Leslie M Hicks
Post-translational modifications (PTMs) are covalent modifications to protein residues which may alter both conformation and activity, thereby modulating signaling and metabolic processes. While PTMs have been largely investigated independently, examination into how different modification interact, or crosstalk, will reveal a more complete understanding of the reciprocity of signaling cascades across numerous pathways. Combinatorial reversible thiol oxidation and phosphorylation in eukaryotes is largely recognized, but rigorous approaches for experimental discovery are underdeveloped...
April 4, 2018: Redox Biology
Dohyeong Kwon, Hiromi Sesaki, Suk-Jo Kang
Stimulator of IFN genes (STING) is essential for the DNA-sensing innate immune pathway. Recently, evidence is emerging that suggests STING also plays important roles in autoimmunity, cancer therapy, and senescence. Although a multitude of post-translational modifications that regulate the STING pathway have been discovered, the cellular events that guide STING translocation remain unclear. Here, we show, paradoxically, that both BAPTA-AM-mediated calcium depletion and ionomycin-induced calcium elevation suppress STING translocation and STING-mediated IFN-β production...
April 16, 2018: Biochemical and Biophysical Research Communications
Emma Bondy-Chorney, Alix Denoncourt, Yuka Sai, Michael Downey
Lysine acetylation is a critical post-translation modification that can impact a protein's localization, stability and function. Originally thought to only occur on histones, we now know thousands of non-histone proteins are also acetylated. In conjunction with many other proteins, lysine acetyltransferases (KATs) are incorporated into large protein complexes that carry out these modifications. In this review we focus on the contribution of two KATs, KAT2A and KAT2B, and their potential roles in the development and progression of cancer...
April 19, 2018: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
Walter R Drake, Ching-Wen Hou, Natasha E Zachara, Catherine Leimkuhler Grimes
O-GlcNAcylation is a dynamic and functionally diverse post-translational modification shown to affect thousands of proteins, including the innate immune receptor nucleotide-binding oligomerization domain-containing protein 2 (Nod2). Mutations of Nod2 (R702W, G908R and 1007 fs) are associated with Crohn's disease and have lower stabilities compared to wild type. Cycloheximide (CHX)-chase half-life assays have been used to show that O-GlcNAcylation increases the stability and response of both wild type and Crohn's variant Nod2, R702W...
April 18, 2018: Journal of Bioenergetics and Biomembranes
Anupama Tuladhar, Kathleen S Rein
The anticancer effect of manumycin A (Man A) has been attributed to the inhibition of farnesyl transferase (FTase), an enzyme that is responsible for post-translational modification of Ras proteins. However, we have discovered that Man A inhibits mammalian cytosolic thioredoxin reductase 1 (TrxR-1) in a time-dependent manner, with an IC50 of 272 nM with preincubation and 1586 nM without preincubation. The inhibition of TrxR-1 by Man A is irreversible and is the result of a covalent interaction between Man A and TrxR-1...
April 12, 2018: ACS Medicinal Chemistry Letters
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