scholarly journals Structure, Activity, and Function of the Protein Lysine Methyltransferase G9a

Life ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1082
Author(s):  
Coralie Poulard ◽  
Lara M. Noureddine ◽  
Ludivine Pruvost ◽  
Muriel Le Romancer
Keyword(s):  
Transcriptional Repression ◽  
Cancer Biology ◽  
Structural Features ◽  
Cellular Mechanisms ◽  
Post Translational Modifications ◽  
Structure Activity ◽  
Lysine Residues ◽  
Lysine Methyltransferase ◽  
And Function ◽  
Insight Into

G9a is a lysine methyltransferase catalyzing the majority of histone H3 mono- and dimethylation at Lys-9 (H3K9), responsible for transcriptional repression events in euchromatin. G9a has been shown to methylate various lysine residues of non-histone proteins and acts as a coactivator for several transcription factors. This review will provide an overview of the structural features of G9a and its paralog called G9a-like protein (GLP), explore the biochemical features of G9a, and describe its post-translational modifications and the specific inhibitors available to target its catalytic activity. Aside from its role on histone substrates, the review will highlight some non-histone targets of G9a, in order gain insight into their role in specific cellular mechanisms. Indeed, G9a was largely described to be involved in embryonic development, hypoxia, and DNA repair. Finally, the involvement of G9a in cancer biology will be presented.

scholarly journals Significance of Mast Cell Formed Extracellular Traps in Microbial Defense

2021 ◽  
Author(s):  
Daniel Elieh Ali Komi ◽  
Wolfgang M. Kuebler
Keyword(s):  
State Of The Art ◽  
Extracellular Dna ◽  
Cellular Mechanisms ◽  
Extracellular Traps ◽  
Synthetic Chemicals ◽  
Dna Strands ◽  
Associated Proteins ◽  
Microbial Defense ◽  
And Function ◽  
Insight Into

AbstractMast cells (MCs) are critically involved in microbial defense by releasing antimicrobial peptides (such as cathelicidin LL-37 and defensins) and phagocytosis of microbes. In past years, it has become evident that in addition MCs may eliminate invading pathogens by ejection of web-like structures of DNA strands embedded with proteins known together as extracellular traps (ETs). Upon stimulation of resting MCs with various microorganisms, their products (including superantigens and toxins), or synthetic chemicals, MCs become activated and enter into a multistage process that includes disintegration of the nuclear membrane, release of chromatin into the cytoplasm, adhesion of cytoplasmic granules on the emerging DNA web, and ejection of the complex into the extracellular space. This so-called ETosis is often associated with cell death of the producing MC, and the type of stimulus potentially determines the ratio of surviving vs. killed MCs. Comparison of different microorganisms with specific elimination characteristics such as S pyogenes (eliminated by MCs only through extracellular mechanisms), S aureus (removed by phagocytosis), fungi, and parasites has revealed important aspects of MC extracellular trap (MCET) biology. Molecular studies identified that the formation of MCET depends on NADPH oxidase-generated reactive oxygen species (ROS). In this review, we summarize the present state-of-the-art on the biological relevance of MCETosis, and its underlying molecular and cellular mechanisms. We also provide an overview over the techniques used to study the structure and function of MCETs, including electron microscopy and fluorescence microscopy using specific monoclonal antibodies (mAbs) to detect MCET-associated proteins such as tryptase and histones, and cell-impermeant DNA dyes for labeling of extracellular DNA. Comparing the type and biofunction of further MCET decorating proteins with ETs produced by other immune cells may help provide a better insight into MCET biology in the pathogenesis of autoimmune and inflammatory disorders as well as microbial defense.

scholarly journals Structure and function of factor XI

Blood ◽  
2010 ◽  
Vol 115 (13) ◽  
pp. 2569-2577 ◽  
Author(s):  
Jonas Emsley ◽  
Paul A. McEwan ◽  
David Gailani
Keyword(s):  
Catalytic Domain ◽  
Structural Features ◽  
Factor Ix ◽  
Missense Mutations ◽  
Factor Xi ◽  
Disk Structure ◽  
Ligand Binding Sites ◽  
And Function ◽  
Insight Into

AbstractFactor XI (FXI) is the zymogen of an enzyme (FXIa) that contributes to hemostasis by activating factor IX. Although bleeding associated with FXI deficiency is relatively mild, there has been resurgence of interest in FXI because of studies indicating it makes contributions to thrombosis and other processes associated with dysregulated coagulation. FXI is an unusual dimeric protease, with structural features that distinguish it from vitamin K–dependent coagulation proteases. The recent availability of crystal structures for zymogen FXI and the FXIa catalytic domain have enhanced our understanding of structure-function relationships for this molecule. FXI contains 4 “apple domains” that form a disk structure with extensive interfaces at the base of the catalytic domain. The characterization of the apple disk structure, and its relationship to the catalytic domain, have provided new insight into the mechanism of FXI activation, the interaction of FXIa with the substrate factor IX, and the binding of FXI to platelets. Analyses of missense mutations associated with FXI deficiency have provided additional clues to localization of ligand-binding sites on the protein surface. Together, these data will facilitate efforts to understand the physiology and pathology of this unusual protease, and development of therapeutics to treat thrombotic disorders.

scholarly journals Integration of Sugar Metabolism and Proteoglycan Synthesis by UDP-glucose Dehydrogenase

2020 ◽  
Vol 69 (1) ◽  
pp. 13-23 ◽  
Author(s):  
Brenna M. Zimmer ◽  
Joseph J. Barycki ◽  
Melanie A. Simpson
Keyword(s):  
Glucose Dehydrogenase ◽  
Sugar Metabolism ◽  
Structural Features ◽  
Proteoglycan Synthesis ◽  
Allosteric Modulators ◽  
Uridine Diphosphate ◽  
Cellular Mechanisms ◽  
Glycosaminoglycan Synthesis ◽  
Post Translational Modifications ◽  
Multiple Levels

Regulation of proteoglycan and glycosaminoglycan synthesis is critical throughout development, and to maintain normal adult functions in wound healing and the immune system, among others. It has become increasingly clear that these processes are also under tight metabolic control and that availability of carbohydrate and amino acid metabolite precursors has a role in the control of proteoglycan and glycosaminoglycan turnover. The enzyme uridine diphosphate (UDP)-glucose dehydrogenase (UGDH) produces UDP-glucuronate, an essential precursor for new glycosaminoglycan synthesis that is tightly controlled at multiple levels. Here, we review the cellular mechanisms that regulate UGDH expression, discuss the structural features of the enzyme, and use the structures to provide a context for recent studies that link post-translational modifications and allosteric modulators of UGDH to its function in downstream pathways:

scholarly journals Post-translational modifications of PRC2: signals directing its activity

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Yiqi Yang ◽  
Gang Li
Keyword(s):  
Catalytic Activity ◽  
Transcriptional Repression ◽  
Essential Role ◽  
Histone H3 ◽  
Post Translational Modifications ◽  
Polycomb Repressive Complex 2 ◽  
Cellular Identity ◽  
Organismal Development ◽  
Biochemical Signals ◽  
Insight Into

Abstract Polycomb repressive complex 2 (PRC2) is a chromatin-modifying enzyme that catalyses the methylation of histone H3 at lysine 27 (H3K27me1/2/3). This complex maintains gene transcriptional repression and plays an essential role in the maintenance of cellular identity as well as normal organismal development. The activity of PRC2, including its genomic targeting and catalytic activity, is controlled by various signals. Recent studies have revealed that these signals involve cis chromatin features, PRC2 facultative subunits and post-translational modifications (PTMs) of PRC2 subunits. Overall, these findings have provided insight into the biochemical signals directing PRC2 function, although many mysteries remain.

Lysine modifications and autophagy

2012 ◽  
Vol 52 ◽  
pp. 65-77 ◽  
Author(s):  
Kristi L. Norris ◽  
Tso-Pang Yao
Keyword(s):  
Cellular Stress ◽  
Nutrient Deprivation ◽  
Substrate Selectivity ◽  
Catabolic Pathway ◽  
Post Translational Modifications ◽  
Cellular Processes ◽  
Lysine Residues ◽  
Clinical Potential ◽  
Insight Into

Nutrient deprivation or cellular stress leads to the activation of a catabolic pathway that is conserved across species, known as autophagy. This process is considered to be adaptive and plays an important role in a number of cellular processes, including metabolism, immunity and development. Autophagy has also been linked to diseases, such as cancer and neurodegeneration, highlighting the importance of a better insight into its regulation. In the present chapter, we discuss how PTMs (post-translational modifications) of lysine residues by acetylation and ubiquitination alter the function of key proteins involved in the activation, maturation and substrate selectivity of autophagy. We also discuss the clinical potential of targeting these modifications to modulate autophagic activities.

scholarly journals Structural Insight into the Binding of TGIF1 to SIN3A PAH2 Domain through a C-Terminal Amphipathic Helix

2021 ◽  
Vol 22 (23) ◽  
pp. 12631
Author(s):  
Xiaoling He ◽  
Yao Nie ◽  
Heng Zhou ◽  
Rui Hu ◽  
Ying Li ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Structural Basis ◽  
Hydrophobic Core ◽  
Amphipathic Helix ◽  
Structural Insight ◽  
Function Relationship ◽  
And Function ◽  
Key Residues ◽  
Hydrophobic Cleft ◽  
Insight Into

TGIF1 is a transcriptional repressor playing crucial roles in human development and function and is associated with holoprosencephaly and various cancers. TGIF1-directed transcriptional repression of specific genes depends on the recruitment of corepressor SIN3A. However, to date, the exact region of TGIF1 binding to SIN3A was not clear, and the structural basis for the binding was unknown. Here, we demonstrate that TGIF1 utilizes a C-terminal domain (termed as SIN3A-interacting domain, SID) to bind with SIN3A PAH2. The TGIF1 SID adopts a disordered structure at the apo state but forms an amphipathic helix binding into the hydrophobic cleft of SIN3A PAH2 through the nonpolar side at the holo state. Residues F379, L382 and V383 of TGIF1 buried in the hydrophobic core of the complex are critical for the binding. Moreover, homodimerization of TGIF1 through the SID and key residues of F379, L382 and V383 was evidenced, which suggests a dual role of TGIF1 SID and a correlation between dimerization and SIN3A-PAH2 binding. This study provides a structural insight into the binding of TGIF1 with SIN3A, improves the knowledge of the structure–function relationship of TGIF1 and its homologs and will help in recognizing an undiscovered SIN3A-PAH2 binder and developing a peptide inhibitor for cancer treatment.

scholarly journals Design and Construction of a Focused DNA-Encoded Library for Multivalent Chromatin Reader Proteins

Molecules ◽  
2020 ◽  
Vol 25 (4) ◽  
pp. 979 ◽  
Author(s):  
Justin M. Rectenwald ◽  
Shiva Krishna Reddy Guduru ◽  
Zhao Dang ◽  
Leonard B. Collins ◽  
Yi-En Liao ◽  
...  
Keyword(s):  
Structure And Function ◽  
Cellular Phenotype ◽  
Chemical Probes ◽  
Target Class ◽  
High Quality ◽  
Histone Tails ◽  
Post Translational Modifications ◽  
Chromatin Dynamics ◽  
And Function ◽  
Insight Into

Chromatin structure and function, and consequently cellular phenotype, is regulated in part by a network of chromatin-modifying enzymes that place post-translational modifications (PTMs) on histone tails. These marks serve as recruitment sites for other chromatin regulatory complexes that ‘read’ these PTMs. High-quality chemical probes that can block reader functions of proteins involved in chromatin regulation are important tools to improve our understanding of pathways involved in chromatin dynamics. Insight into the intricate system of chromatin PTMs and their context within the epigenome is also therapeutically important as misregulation of this complex system is implicated in numerous human diseases. Using computational methods, along with structure-based knowledge, we have designed and constructed a focused DNA-Encoded Library (DEL) containing approximately 60,000 compounds targeting bi-valent methyl-lysine (Kme) reader domains. Additionally, we have constructed DNA-barcoded control compounds to allow optimization of selection conditions using a model Kme reader domain. We anticipate that this target-class focused approach will serve as a new method for rapid discovery of inhibitors for multivalent chromatin reader domains.

scholarly journals Structure of human endo-α-1,2-mannosidase (MANEA), an antiviral host-glycosylation target

2020 ◽  
Vol 117 (47) ◽  
pp. 29595-29601
Author(s):  
Łukasz F. Sobala ◽  
Pearl Z. Fernandes ◽  
Zalihe Hakki ◽  
Andrew J. Thompson ◽  
Jonathon D. Howe ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Antiviral Agents ◽  
Structural Features ◽  
Glycoside Hydrolases ◽  
Host Protein ◽  
Cellular Models ◽  
Mechanistic Basis ◽  
And Function ◽  
Insight Into ◽  
Mammalian Protein

Mammalian protein N-linked glycosylation is critical for glycoprotein folding, quality control, trafficking, recognition, and function. N-linked glycans are synthesized from Glc3Man9GlcNAc2precursors that are trimmed and modified in the endoplasmic reticulum (ER) and Golgi apparatus by glycoside hydrolases and glycosyltransferases. Endo-α-1,2-mannosidase (MANEA) is the soleendo-acting glycoside hydrolase involved in N-glycan trimming and is located within the Golgi, where it allows ER-escaped glycoproteins to bypass the classical N-glycosylation trimming pathway involving ER glucosidases I and II. There is considerable interest in the use of small molecules that disrupt N-linked glycosylation as therapeutic agents for diseases such as cancer and viral infection. Here we report the structure of the catalytic domain of human MANEA and complexes with substrate-derived inhibitors, which provide insight into dynamic loop movements that occur on substrate binding. We reveal structural features of the human enzyme that explain its substrate preference and the mechanistic basis for catalysis. These structures have inspired the development of new inhibitors that disrupt host protein N-glycan processing of viral glycans and reduce the infectivity of bovine viral diarrhea and dengue viruses in cellular models. These results may contribute to efforts aimed at developing broad-spectrum antiviral agents and help provide a more in-depth understanding of the biology of mammalian glycosylation.

scholarly journals Identification of the Protein Glycation Sites in Human Myoglobin as Rapidly Induced by d-Ribose

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 5829
Author(s):  
Jing-Jing Liu ◽  
Yong You ◽  
Shu-Qin Gao ◽  
Shuai Tang ◽  
Lei Chen ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
High Performance ◽  
Protein Glycation ◽  
Valuable Insight ◽  
Liquid Chromatography Mass Spectrometry ◽  
Post Translational Modification ◽  
Lysine Residues ◽  
Human Myoglobin ◽  
And Function ◽  
Insight Into

Protein glycation is an important protein post-translational modification and is one of the main pathogenesis of diabetic angiopathy. Other than glycated hemoglobin, the protein glycation of other globins such as myoglobin (Mb) is less studied. The protein glycation of human Mb with ribose has not been reported, and the glycation sites in the Mb remain unknown. This article reports that d-ribose undergoes rapid protein glycation of human myoglobin (HMb) at lysine residues (K34, K87, K56, and K147) on the protein surface, as identified by ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) and electrospray ionization tandem mass spectrometry (ESI-MS/MS). Moreover, glycation by d-ribose at these sites slightly decreased the rate of the met heme (FeIII) in reaction with H2O2 to form a ferryl heme (FeIV=O). This study provides valuable insight into the protein glycation by d-ribose and provides a foundation for studying the structure and function of glycated heme proteins.

scholarly journals Structure, Activity and Function of the NSD3 Protein Lysine Methyltransferase

Life ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 726
Author(s):  
Philipp Rathert
Keyword(s):  
Current Knowledge ◽  
Histone H3 ◽  
Set Domain ◽  
Histone Methyltransferases ◽  
Structure Activity ◽  
Lysine Methyltransferase ◽  
Active Transcription ◽  
Biochemical Mechanisms ◽  
And Function ◽  
Tumor Types

NSD3 is one of six H3K36-specific lysine methyltransferases in metazoans, and the methylation of H3K36 is associated with active transcription. NSD3 is a member of the nuclear receptor-binding SET domain (NSD) family of histone methyltransferases together with NSD1 and NSD2, which generate mono- and dimethylated lysine on histone H3. NSD3 is mutated and hyperactive in some human cancers, but the biochemical mechanisms underlying such dysregulation are barely understood. In this review, the current knowledge of NSD3 is systematically reviewed. Finally, the molecular and functional characteristics of NSD3 in different tumor types according to the current research are summarized.

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