Mitochondrial aminoacyl-tRNA synthetases

Chihade, Joseph

doi:10.1016/bs.enz.2020.07.003

Cited by 9 publications

(8 citation statements)

References 93 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Experiments found that certain mutations in hmPheRS's anticodon binding domain (ABD) can significantly affect the catalytic efficiency of its active sites in the catalytic domain (CAD), although the two sites are separated by ≤80 Å. 6,7 Structural studies, including ours, suggest the conformational flexibility of the functional regions and the long-range allosteric couplings between the domains are essential for hmPheRS's aminoacylation activity. 9,10 With regard to allostery, recent findings show it is entropic in nature and depends on the information transfer between two sites through residues' coordinated fluctuations.…”

mentioning

confidence: 85%

“…In particular, the N-terminal region, which is in contact with tRNA in the aminoacylation reaction and plays a key role in signal transmission, is shown to be a strong entropy sink or acceptor (Figure D). For the bottom structural fragment, the characteristic region of hmPheRS is vital for enhancing long-range allosteric coupling of CAD with ABD, , and its entropy-accepting behavior is also well highlighted (Figure D). Thus, dfcfGNM MD can clearly distinguish the allosterically driving and driven regions.…”

mentioning

confidence: 95%

“…Aminoacyl-tRNA synthetases (aaRSes) are the universally distributed enzymes that play a crucial role in genetic code translation by means of covalent attachment of amino acids to their cognate tRNAs . Human mitochondrial phenylalanyl-tRNA synthetase (hmPheRS), because it has a minimum set of structural domains capable of aminoacylation and being involved in various central nervous system (CNS) diseases like autosomal recessive spastic paraplegia, epileptic encephalopathy, infantile mitochondrial Alpers encephalopathy, etc., − has attracted a great deal of attention. − …”

mentioning

confidence: 99%

See 2 more Smart Citations

Study of the Allosteric Mechanism of Human Mitochondrial Phenylalanyl-tRNA Synthetase by Transfer Entropy via an Improved Gaussian Network Model and Co-evolution Analyses

Han

Wang

et al. 2023

J. Phys. Chem. Lett.

View full text Add to dashboard Cite

We propose an improved transfer entropy approach called the dynamic version of the force constant fitted Gaussian network model based on molecular dynamics ensemble (dfcfGNM MD ) to explore the allosteric mechanism of human mitochondrial phenylalanyl-tRNA synthetase (hmPheRS), one of the aminoacyl-tRNA synthetases that play a crucial role in translation of the genetic code. The dfcfGNM MD method can provide reliable estimates of the transfer entropy and give new insights into the role of the anticodon binding domain in driving the catalytic domain in aminoacylation activity and into the effects of tRNA binding and residue mutation on the enzyme activity, revealing the causal mechanism of the allosteric communication in hmPheRS. In addition, we incorporate the residue dynamic and co-evolutionary information to further investigate the key residues in hmPheRS allostery. This study sheds light on the mechanisms of hmPheRS allostery and can provide important information for related drug design.A minoacyl-tRNA synthetases (aaRSes) are the universally distributed enzymes that play a crucial role in genetic code translation by means of covalent attachment of amino acids to their cognate tRNAs. 1 Human mitochondrial phenylalanyl-tRNA synthetase (hmPheRS), because it has a minimum set of structural domains capable of aminoacylation and being involved in various central nervous system (CNS) diseases like autosomal recessive spastic paraplegia, epileptic encephalopathy, infantile mitochondrial Alpers encephalopathy, etc., 2−5 has attracted a great deal of attention. 6−8 hmPheRS with a single chain is the smallest known member of class II aaRS. The structures of hmPheRS in tRNA-free and -bound states have been experimentally determined, which are composed of four major functional regions and several motifs as shown in Figure 1. The corresponding function annotations are listed in Table 1. Experiments found that certain mutations in hmPheRS's anticodon binding domain (ABD) can significantly affect the catalytic efficiency of its active sites in the catalytic domain (CAD), although the two sites are separated by ≤80 Å. 6,7 Structural studies, including ours, suggest the conformational flexibility of the functional regions and the long-range allosteric couplings between the domains are essential for hmPheRS's aminoacylation activity. 9,10 With regard to allostery, recent findings show it is entropic in nature and depends on the information transfer between two sites through residues' coordinated fluctuations. 11 Currently, the molecular mechanism by which the long-range allosteric

show abstract

mentioning

confidence: 85%

mentioning

confidence: 95%

mentioning

confidence: 99%

See 1 more Smart Citation

Study of the Allosteric Mechanism of Human Mitochondrial Phenylalanyl-tRNA Synthetase by Transfer Entropy via an Improved Gaussian Network Model and Co-evolution Analyses

Han

Wang

et al. 2023

J. Phys. Chem. Lett.

View full text Add to dashboard Cite

show abstract

“…GlyRS-B is an α 2 β 2 tetrameric Class II AARS found in bacteria and chloroplasts 21 . It is distinct from the homodimeric GlyRS-A found in archaea, eukaryotes, and some bacteria 3, 22 . GlyRS-B usually occurs as an α 2 β 2 heterotetramer, with glycine activation being performed by the short α chains.…”

Section: Introductionmentioning

confidence: 96%

Genomic database furnishes a spontaneous example of a functional Class II glycyl-tRNA synthetase urzyme

Patra,

Douglas,

Wills

et al. 2024

Preprint

View full text Add to dashboard Cite

The chief barrier to studies of how genetic coding emerged is the lack of experimental models for ancestral aminoacyl-tRNA synthetases (AARS). We hypothesized that conserved core catalytic sites could represent such ancestors. That hypothesis enabled engineering functional urzymes from TrpRS, LeuRS, and HisRS. We describe here a fourth urzyme, GlyCA, detected in an open reading frame from the genomic record of the arctic fox, Vulpes lagopus. GlyCA is homologous to a bacterial heterotetrameric Class II GlyRS-B. Alphafold2 predicted that the N-terminal 81 amino acids would adopt a 3D structure nearly identical to the HisRS urzyme (HisCA1). We expressed and purified that N-terminal segment. Enzymatic characterization revealed a robust single-turnover burst size and a catalytic rate for ATP consumption well in excess of that previously published for HisCA1. Time-dependent aminoacylation of tRNAGly proceeds at a rate consistent with that observed for amino acid activation. In fact, GlyCA is actually 35 times more active in glycine activation by ATP than the full-length GlyRS-B α-subunit dimer. ATP-dependent activation of the 20 canonical amino acids favors Class II amino acids that complement those favored by HisCA and LeuAC. These properties reinforce the notion that urzymes represent the requisite ancestral catalytic activities to implement a reduced genetic coding alphabet.

show abstract

“…Mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) are a family of enzymes that are encoded by the nuclear genome, translated by cytosolic ribosomes, and imported into the mitochondria where they charge specific tRNAs for protein synthesis [ 1 ]. Thirteen mitochondrial DNA (mt-DNA) encoded proteins are synthesized via the mitochondrial translation machinery.…”

Section: Introductionmentioning

confidence: 99%

Neuropathy-associated Fars2 deficiency affects neuronal development and potentiates neuronal apoptosis by impairing mitochondrial function

Chen

Liu

et al. 2022

Cell Biosci

View full text Add to dashboard Cite

Background Neurodegenerative diseases encompass an extensive and heterogeneous group of nervous system disorders which are characterized by progressive degeneration and death of neurons. Many lines of evidence suggest the participation of mitochondria dysfunction in these diseases. Mitochondrial phenylalanyl-tRNA synthetase, encoded by FARS2, catalyzes the transfer of phenylalanine to its cognate tRNA for protein synthesis. As a member of mt-aaRSs genes, FARS2 missense homozygous mutation c.424G > T (p.D142Y) found in a Chinese consanguineous family first built the relationship between pure hereditary spastic paraplegia (HSP) and FARS2 gene. More FARS2 variations were subsequently found to cause heterogeneous group of neurologic disorders presenting three main phenotypic manifestations: infantile-onset epileptic mitochondrial encephalopathy, later-onset spastic paraplegia and juvenile onset refractory epilepsy. Studies showed that aminoacylation activity is frequently disrupt in cases with FARS2 mutations, indicating a loss-of-function mechanism. However, the underlying pathogenesis of neuropathy-associated Fars2 deficiency is still largely unknown. Results Early gestation lethality of global Fars2 knockout mice was observed prior to neurogenesis. The conditional Fars2 knockout-mouse model delayed lethality to late-gestation, resulting in a thinner cortex and an enlarged ventricle which is consist with the MRI results revealing cortical atrophy and reduced cerebral white matter volume in FARS2-deficient patients. Delayed development of neurite outgrowth followed by neuronal apoptosis was confirmed in Fars2-knockdown mouse primary cultured neurons. Zebrafish, in which fars2 was knocked down, exhibited aberrant motor neuron function including reduced locomotor capacity which well restored the spastic paraplegia phenotype of FARS2-deficient patients. Altered mitochondrial protein synthesis and reduced levels of oxidative phosphorylation complexes were detected in Fars2-deficient samples. And thus, reduced ATP, total NAD levels and mitochondrial membrane potential, together with increased ROS production, revealed mitochondrial dysfunction both in vitro and in vivo. Dctn3 is a potential downstream molecule in responds to Fars2 deficient in neurons, which may provide some evidence for the development of pathogenesis study and therapeutic schedule. Conclusions The Fars2 deficiency genetic models developed in this study cover the typical clinical manifestations in FARS2 patients, and help clarify how neuropathy-associated Fars2 deficiency, by damaging the mitochondrial respiratory chain and impairing mitochondrial function, affects neuronal development and potentiates neuronal cell apoptosis.

show abstract

Mitochondrial aminoacyl-tRNA synthetases

Cited by 9 publications

References 93 publications

Study of the Allosteric Mechanism of Human Mitochondrial Phenylalanyl-tRNA Synthetase by Transfer Entropy via an Improved Gaussian Network Model and Co-evolution Analyses

Study of the Allosteric Mechanism of Human Mitochondrial Phenylalanyl-tRNA Synthetase by Transfer Entropy via an Improved Gaussian Network Model and Co-evolution Analyses

Genomic database furnishes a spontaneous example of a functional Class II glycyl-tRNA synthetase urzyme

Neuropathy-associated Fars2 deficiency affects neuronal development and potentiates neuronal apoptosis by impairing mitochondrial function

Contact Info

Product

Resources

About