Structural and functional insights into peptidyl-tRNA hydrolase

Sharma, Sujata; Kaushik, Saroj; Sinha, Mau; Kushwaha, G.S.; Singh, Avinash; Sikarwar, J.; Chaudhary, Ashvanee Kumar; Gupta, Akshita; Kaur, Punit

doi:10.1016/j.bbapap.2014.04.012

Cited by 36 publications

(24 citation statements)

References 38 publications

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“…Peptidyl-tRNA hydrolase (Pth) is an essential esterase of all bacterial species that recycles free peptidyl-tRNA molecules released during premature termination of translation ( Sharma et al., 2014 ). A variety of factors frequently perturb translation, leading to ribosome stalling.…”

Section: Resultsmentioning

confidence: 99%

A Salmonella Toxin Promotes Persister Formation through Acetylation of tRNA

et al. 2016

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SummaryThe recalcitrance of many bacterial infections to antibiotic treatment is thought to be due to the presence of persisters that are non-growing, antibiotic-insensitive cells. Eventually, persisters resume growth, accounting for relapses of infection. Salmonella is an important pathogen that causes disease through its ability to survive inside macrophages. After macrophage phagocytosis, a significant proportion of the Salmonella population forms non-growing persisters through the action of toxin-antitoxin modules. Here we reveal that one such toxin, TacT, is an acetyltransferase that blocks the primary amine group of amino acids on charged tRNA molecules, thereby inhibiting translation and promoting persister formation. Furthermore, we report the crystal structure of TacT and note unique structural features, including two positively charged surface patches that are essential for toxicity. Finally, we identify a detoxifying mechanism in Salmonella wherein peptidyl-tRNA hydrolase counteracts TacT-dependent growth arrest, explaining how bacterial persisters can resume growth.

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Section: Resultsmentioning

confidence: 99%

A Salmonella Toxin Promotes Persister Formation through Acetylation of tRNA

et al. 2016

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“…Three of these genes are VIPs: C5orf32 that encodes a cysteine-rich transmembrane module with a role in stress tolerance across eukaryotes [ 109 ]; CYB5R1 , which codes for the cytochrome b5 reductase, is overexpressed in DS and its increased expression is associated with higher oxidative stress [ 100 ]; and MPST , which codes for mercaptopyruvate sulfurtransferase, an antioxidant protein [ 110 ]. The three high-hubs are: PTRH1 , coding for a peptidyl RNA hidrolase involved in the rapid clearing of peptidyl-t-RNA, thus preventing cell death [ 111 ]; PPP1R14C , that codes for a protein phosphatase involved cell cycle and metabolism control [ 112 ]; and MORN4 that codes for a MORN-repeat containing protein regulating Ca2+ homeostasis [ 113 , 114 ].…”

Section: Resultsmentioning

confidence: 99%

Modular transcriptional repertoire and MicroRNA target analyses characterize genomic dysregulation in the thymus of Down syndrome infants

et al. 2016

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Trisomy 21-driven transcriptional alterations in human thymus were characterized through gene coexpression network (GCN) and miRNA-target analyses. We used whole thymic tissue - obtained at heart surgery from Down syndrome (DS) and karyotipically normal subjects (CT) - and a network-based approach for GCN analysis that allows the identification of modular transcriptional repertoires (communities) and the interactions between all the system's constituents through community detection. Changes in the degree of connections observed for hierarchically important hubs/genes in CT and DS networks corresponded to community changes. Distinct communities of highly interconnected genes were topologically identified in these networks. The role of miRNAs in modulating the expression of highly connected genes in CT and DS was revealed through miRNA-target analysis. Trisomy 21 gene dysregulation in thymus may be depicted as the breakdown and altered reorganization of transcriptional modules. Leading networks acting in normal or disease states were identified. CT networks would depict the “canonical” way of thymus functioning. Conversely, DS networks represent a “non-canonical” way, i.e., thymic tissue adaptation under trisomy 21 genomic dysregulation. This adaptation is probably driven by epigenetic mechanisms acting at chromatin level and through the miRNA control of transcriptional programs involving the networks' high-hierarchy genes.

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“…PTRH2 , also known as BIT1 (Bcl‐2 inhibitor of transcription 1), is an evolutionarily highly conserved protein that belongs to a family of peptidyl tRNA hydrolases. It prevents the accumulation of prematurely dissociated peptidyl‐tRNA, which could inhibit protein synthesis and be toxic to cells (Sharma et al, ; Yao et al, ). PTRH2 is located in the mitochondria where it participates in protein synthesis via its hydrolase activity.…”

Section: Introductionmentioning

confidence: 99%

Homozygous mutation in PTRH2 gene causes progressive sensorineural deafness and peripheral neuropathy

Sharkia

Shalev

Zalan

et al. 2017

American J of Med Genetics Pt A

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PTRH2 is an evolutionarily highly conserved mitochondrial protein that belongs to a family of peptidyl-tRNA hydrolases. Recently, patients from two consanguineous families with mutations in the PTRH2 gene were reported. Global developmental delay associated with microcephaly, growth retardation, progressive ataxia, distal muscle weakness with ankle contractures, demyelinating sensorimotor neuropathy, and sensorineural hearing loss were present in all patients, while facial dysmorphism with widely spaced eyes, exotropia, thin upper lip, proximally placed thumbs, and deformities of the fingers and toes were present in some individuals. Here, we report a new family with three siblings affected by sensorineural hearing loss and peripheral neuropathy. Autozygosity mapping followed by exome sequencing identified a previously reported homozygous missense mutation in PTRH2 (c.254A>C; p.(Gln85Pro)). Sanger sequencing confirmed that the variant segregated with the phenotype. In contrast to the previously reported patient, the affected siblings had normal intelligence, milder microcephaly, delayed puberty, myopia, and moderate insensitivity to pain. Our findings expand the clinical phenotype and further demonstrate the clinical heterogeneity related to PTRH2 variants.

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Structural and functional insights into peptidyl-tRNA hydrolase

Cited by 36 publications

References 38 publications

A Salmonella Toxin Promotes Persister Formation through Acetylation of tRNA

A Salmonella Toxin Promotes Persister Formation through Acetylation of tRNA

Modular transcriptional repertoire and MicroRNA target analyses characterize genomic dysregulation in the thymus of Down syndrome infants

Homozygous mutation in PTRH2 gene causes progressive sensorineural deafness and peripheral neuropathy

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