Bacterial peptidoglycan with amidated meso-diaminopimelic acid evades NOD1 recognition: an insight into NOD1 structure–recognition

2016 ◽  
Vol 473 (24) ◽  
pp. 4573-4592 ◽  
Author(s):  
Sukhithasri Vijayrajratnam ◽  
Anju Choorakottayil Pushkaran ◽  
Aathira Balakrishnan ◽  
Anil Kumar Vasudevan ◽  
Raja Biswas ◽  
...  
Keyword(s):  
Hot Spot ◽  
Recognition Site ◽  
Diaminopimelic Acid ◽  
Computational Techniques ◽  
Biomolecular Recognition ◽  
Recognition Mechanism ◽  
Structure Recognition ◽  
Evolutionarily Conserved ◽  
Bacterial Peptidoglycan ◽  
Relationship Of

Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is an intracellular pattern recognition receptor that recognizes bacterial peptidoglycan (PG) containing meso-diaminopimelic acid (mesoDAP) and activates the innate immune system. Interestingly, a few pathogenic and commensal bacteria modify their PG stem peptide by amidation of mesoDAP (mesoDAPNH2). In the present study, NOD1 stimulation assays were performed using bacterial PG containing mesoDAP (PGDAP) and mesoDAPNH2 (PGDAPNH2) to understand the differences in their biomolecular recognition mechanism. PGDAP was effectively recognized, whereas PGDAPNH2 showed reduced recognition by the NOD1 receptor. Restimulation of the NOD1 receptor, which was initially stimulated with PGDAP using PGDAPNH2, did not show any further NOD1 activation levels than with PGDAP alone. But the NOD1 receptor initially stimulated with PGDAPNH2 responded effectively to restimulation with PGDAP. The biomolecular structure–recognition relationship of the ligand-sensing leucine-rich repeat (LRR) domain of human NOD1 (NOD1–LRR) with PGDAP and PGDAPNH2 was studied by different computational techniques to further understand the molecular basis of our experimental observations. The d-Glu–mesoDAP motif of GMTPDAP, which is the minimum essential motif for NOD1 activation, was found involved in specific interactions at the recognition site, but the interactions of the corresponding d-Glu–mesoDAP motif of PGDAPNH2 occur away from the recognition site of the NOD1 receptor. Hot-spot residues identified for effective PG recognition by NOD1–LRR include W820, G821, D826 and N850, which are evolutionarily conserved across different host species. These integrated results thus successfully provided the atomic level and biochemical insights on how PGs containing mesoDAPNH2 evade NOD1–LRR receptor recognition.

Understanding the molecular differential recognition of muramyl peptide ligands by LRR domains of human NOD receptors

2017 ◽  
Vol 474 (16) ◽  
pp. 2691-2711 ◽  
Author(s):  
Sukhithasri Vijayrajratnam ◽  
Anju Choorakottayil Pushkaran ◽  
Aathira Balakrishnan ◽  
Anil Kumar Vasudevan ◽  
Raja Biswas ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Hot Spot ◽  
Three Dimensional ◽  
Docking Studies ◽  
Peptide Ligands ◽  
Recognition Site ◽  
Diaminopimelic Acid ◽  
Ligand Recognition ◽  
Muramyl Peptide ◽  
Differential Recognition

Human nucleotide-binding oligomerization domain proteins, hNOD1 and hNOD2, are host intracellular receptors with C-terminal leucine-rich repeat (LRR) domains, which recognize specific bacterial peptidoglycan (PG) fragments as their ligands. The specificity of this recognition is dependent on the third amino acid of the stem peptide of the PG ligand, which is usually meso-diaminopimelic acid (mesoDAP) or l-lysine (l-Lys). Since the LRR domains of hNOD receptors had been experimentally shown to confer the PG ligand-sensing specificity, we developed three-dimensional structures of hNOD1-LRR and the hNOD2-LRR to understand the mechanism of differential recognition of muramyl peptide ligands by hNOD receptors. The hNOD1-LRR and hNOD2-LRR receptor models exhibited right-handed curved solenoid shape. The hot-spot residues experimentally proved to be critical for ligand recognition were located in the concavity of the NOD-LRR and formed the recognition site. Our molecular docking analyses and molecular electrostatic potential mapping studies explain the activation of hNOD-LRRs, in response to effective molecular interactions of PG ligands at the recognition site; and conversely, the inability of certain PG ligands to activate hNOD-LRRs, by deviations from the recognition site. Based on molecular docking studies using PG ligands, we propose few residues — G825, D826 and N850 in hNOD1-LRR and L904, G905, W931, L932 and S933 in hNOD2-LRR, evolutionarily conserved across different host species, which may play a major role in ligand recognition. Thus, our integrated experimental and computational approach elucidates the molecular basis underlying the differential recognition of PG ligands by hNOD receptors.

scholarly journals Cellular macromolecules-tethered DNA walking indexing to explore nanoenvironments of chromatin modifications

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Feng Chen ◽  
Min Bai ◽  
Xiaowen Cao ◽  
Jing Xue ◽  
Yue Zhao ◽  
...  
Keyword(s):  
Fluorescence Imaging ◽  
Spatial Organization ◽  
High Throughput Sequencing ◽  
Dna Amplification ◽  
Chromatin Modifications ◽  
Dynamic Changes ◽  
Recognition Mechanism ◽  
Cell Cycles ◽  
Dna Modifications ◽  
Relationship Of

AbstractExploring spatial organization and relationship of diverse biomolecules within cellular nanoenvironments is important to elucidate the fundamental processes of life. However, it remains methodologically challenging. Herein, we report a molecular recognition mechanism cellular macromolecules-tethered DNA walking indexing (Cell-TALKING) to probe the nanoenvironments containing diverse chromatin modifications. As an example, we characterize the nanoenvironments of three DNA modifications around one histone posttranslational modification (PTM). These DNA modifications in fixed cells are labeled with respective DNA barcoding probes, and then the PTM site is tethered with a DNA walking probe. Cell-TALKING can continuously produce cleavage records of any barcoding probes nearby the walking probe. New 3’-OH ends are generated on the cleaved barcoding probes to induce DNA amplification for downstream detections. Combining fluorescence imaging, we identify various combinatorial chromatin modifications and investigate their dynamic changes during cell cycles. We also explore the nanoenvironments in different cancer cell lines and clinical specimens. In principle, using high-throughput sequencing instead of fluorescence imaging may allow the detection of complex cellular nanoenvironments containing tens of biomolecules such as transcription factors.

scholarly journals Disassembly of theStaphylococcus aureushibernating 100S ribosome by an evolutionarily conserved GTPase

2017 ◽  
Vol 114 (39) ◽  
pp. E8165-E8173 ◽  
Author(s):  
Arnab Basu ◽  
Mee-Ngan F. Yap
Keyword(s):  
Opportunistic Pathogen ◽  
Dependent Manner ◽  
Bacterial Survival ◽  
Temperature Dependent ◽  
Bacterial Phyla ◽  
Evolutionarily Conserved ◽  
Bona Fide ◽  
70S Ribosome ◽  
Relationship Of ◽  
Dissociation Factor

The bacterial hibernating 100S ribosome is a poorly understood form of the dimeric 70S particle that has been linked to pathogenesis, translational repression, starvation responses, and ribosome turnover. In the opportunistic pathogenStaphylococcus aureusand most other bacteria, hibernation-promoting factor (HPF) homodimerizes the 70S ribosomes to form a translationally silent 100S complex. Conversely, the 100S ribosomes dissociate into subunits and are presumably recycled for new rounds of translation. The regulation and disassembly of the 100S ribosome are largely unknown because the temporal abundance of the 100S ribosome varies considerably among different bacterial phyla. Here, we identify a universally conserved GTPase (HflX) as a bona fide dissociation factor of theS. aureus100S ribosome. The expression levelshpfandhflXare coregulated by general stress and stringent responses in a temperature-dependent manner. While all tested guanosine analogs stimulate the splitting activity of HflX on the 70S ribosome, only GTP can completely dissociate the 100S ribosome. Our results reveal the antagonistic relationship of HPF and HflX and uncover the key regulators of 70S and 100S ribosome homeostasis that are intimately associated with bacterial survival.

scholarly journals The relationship of thermodynamic stability at a G•U recognition site to tRNA aminoacylation specificity

RNA ◽  
1999 ◽  
Vol 5 (11) ◽  
pp. 1490-1494 ◽  
Author(s):  
PETER STRAZEWSKI ◽  
EWA BIALA ◽  
KAY GABRIEL ◽  
WILLIAM H. McCLAIN
Keyword(s):  
Thermodynamic Stability ◽  
Recognition Site ◽  
Trna Aminoacylation ◽  
Relationship Of ◽  
The Relationship

scholarly journals Mitophagy as a stress response in mammalian cells and in respiring S. cerevisiae

2016 ◽  
Vol 44 (2) ◽  
pp. 541-545 ◽  
Author(s):  
Hagai Abeliovich ◽  
Jörn Dengjel
Keyword(s):  
Mammalian Cells ◽  
Late Onset ◽  
Specific Form ◽  
Mitochondrial Quality Control ◽  
Evolutionarily Conserved ◽  
Autophagic Degradation ◽  
Relationship Of ◽  
To Receive ◽  
The Relationship ◽  
Significant Attention

The degradation of malfunctioning or superfluous mitochondria in the lysosome/vacuole is an important housekeeping function in respiring eukaryotic cells. This clearance is thought to occur by a specific form of autophagic degradation called mitophagy, and plays a role in physiological homoeostasis as well as in the progression of late-onset diseases. Although the mechanism of bulk degradation by macroautophagy is relatively well established, the selective autophagic degradation of mitochondria has only recently begun to receive significant attention. In this mini-review, we introduce mitophagy as a form of mitochondrial quality control and proceed to provide specific examples from yeast and mammalian systems. We then discuss the relationship of mitophagy to mitochondrial stress, and provide a broad mechanistic overview of the process with an emphasis on evolutionarily conserved pathways.

scholarly journals Drug targeting of aminoacyl-tRNA synthetases in Anopheles species and Aedes aegypti that cause malaria and dengue

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Soumyananda Chakraborti ◽  
Jyoti Chhibber-Goel ◽  
Amit Sharma
Keyword(s):  
Aedes Aegypti ◽  
Drug Targets ◽  
Viral Infections ◽  
Sequence Similarity ◽  
Mosquito Species ◽  
Physicochemical Characteristics ◽  
Computational Techniques ◽  
Trna Synthetases ◽  
Aminoacyl Trna Synthetases ◽  
Relationship Of

Abstract Background Mosquito-borne diseases have a devastating impact on human civilization. A few species of Anopheles mosquitoes are responsible for malaria transmission, and while there has been a reduction in malaria-related deaths worldwide, growing insecticide resistance is a cause for concern. Aedes mosquitoes are known vectors of viral infections, including dengue, yellow fever, chikungunya, and Zika. Aminoacyl-tRNA synthetases (aaRSs) are key players in protein synthesis and are potent anti-infective drug targets. The structure–function activity relationship of aaRSs in mosquitoes (in particular, Anopheles and Aedes spp.) remains unexplored. Methods We employed computational techniques to identify aaRSs from five different mosquito species (Anopheles culicifacies, Anopheles stephensi, Anopheles gambiae, Anopheles minimus, and Aedes aegypti). The VectorBase database (https://vectorbase.org/vectorbase/app) and web-based tools were utilized to predict the subcellular localizations (TargetP-2.0, UniProt, DeepLoc-1.0), physicochemical characteristics (ProtParam), and domain arrangements (PfAM, InterPro) of the aaRSs. Structural models for prolyl (PRS)-, and phenylalanyl (FRS)-tRNA synthetases—were generated using the I-TASSER and Phyre protein modeling servers. Results Among the vector species, a total of 37 (An. gambiae), 37 (An. culicifacies), 37 (An. stephensi), 37 (An. minimus), and 35 (Ae. aegypti) different aaRSs were characterized within their respective mosquito genomes. Sequence identity amongst the aaRSs from the four Anopheles spp. was > 80% and in Ae. aegypti was > 50%. Conclusions Structural analysis of two important aminoacyl-tRNA synthetases [prolyl (PRS) and phenylanalyl (FRS)] of Anopheles spp. suggests structural and sequence similarity with potential antimalarial inhibitor [halofuginone (HF) and bicyclic azetidine (BRD1369)] binding sites. This suggests the potential for repurposing of these inhibitors against the studied Anopheles spp. and Ae. aegypti.

Micromonospora sonneratiae sp. nov., isolated from a root of Sonneratia apetala

2013 ◽  
Vol 63 (Pt_7) ◽  
pp. 2383-2388 ◽  
Author(s):  
Lei Li ◽  
Yi-Li Tang ◽  
Bin Wei ◽  
Qing-Yi Xie ◽  
Zixin Deng ◽  
...  
Keyword(s):  
Biochemical Properties ◽  
Diaminopimelic Acid ◽  
Rrna Gene ◽  
Polar Lipid Profile ◽  
Content Type ◽  
Sonneratia Apetala ◽  
Link Type ◽  
Close Relationship ◽  
Actinomycete Strain ◽  
Relationship Of

A novel endophytic actinomycete, strain 274745T, was isolated from a root of Sonneratia apetala collected in a mangrove forest in Sanya, Hainan province, China. The 16S rRNA gene sequence of strain 274745T showed the greatest similarity to Micromonospora pattaloongensis TJ2-2T (98.3 %). Phylogenetic analysis based on the gyrB gene also supported the close relationship of these two strains. The predominant menaquinone was MK-10(H8) and the major fatty acids were iso-C15 : 0, C17 : 0 and anteiso-C15 : 0. The characteristic whole-cell sugars were xylose and mannose. The cell wall contained meso-diaminopimelic acid and glycine. The polar lipid profile mainly comprised phosphatidylethanolamine, phosphatidylinositol and diphosphatidylglycerol. The DNA G+C content was 71.6 mol%. Furthermore, a combination of DNA–DNA relatedness and some physiological and biochemical properties indicated that the novel strain could be readily distinguished from the closest phylogenetic relatives. On the basis of these phenotypic and genotypic data, strain 274745T represents a novel species of the genus Micromonospora , for which the name Micromonospora sonneratiae sp. nov. is proposed. The type strain is 274745T ( = CCTCC AA 2012003T  = DSM 45704T).

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