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Review
. 2019 Apr 5;294(14):5321-5339.
doi: 10.1074/jbc.REV118.002955. Epub 2019 Jan 14.

Neurodegenerative Charcot-Marie-Tooth disease as a case study to decipher novel functions of aminoacyl-tRNA synthetases

Na Wei  1 , Qian Zhang  1 , Xiang-Lei Yang  2
Affiliations
Review

Neurodegenerative Charcot-Marie-Tooth disease as a case study to decipher novel functions of aminoacyl-tRNA synthetases

Na Wei et al. J Biol Chem. .

Abstract

Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes that catalyze the first reaction in protein biosynthesis, namely the charging of transfer RNAs (tRNAs) with their cognate amino acids. aaRSs have been increasingly implicated in dominantly and recessively inherited human diseases. The most common aaRS-associated monogenic disorder is the incurable neurodegenerative disease Charcot-Marie-Tooth neuropathy (CMT), caused by dominant mono-allelic mutations in aaRSs. With six currently known members (GlyRS, TyrRS, AlaRS, HisRS, TrpRS, and MetRS), aaRSs represent the largest protein family implicated in CMT etiology. After the initial discovery linking aaRSs to CMT, the field has progressed from understanding whether impaired tRNA charging is a critical component of this disease to elucidating the specific pathways affected by CMT-causing mutations in aaRSs. Although many aaRS CMT mutants result in loss of tRNA aminoacylation function, animal genetics studies demonstrated that dominant mutations in GlyRS cause CMT through toxic gain-of-function effects, which also may apply to other aaRS-linked CMT subtypes. The CMT-causing mechanism is likely to be multifactorial and involves multiple cellular compartments, including the nucleus and the extracellular space, where the normal WT enzymes also appear. Thus, the association of aaRSs with neuropathy is relevant to discoveries indicating that aaRSs also have nonenzymatic regulatory functions that coordinate protein synthesis with other biological processes. Through genetic, functional, and structural analyses, commonalities among different mutations and different aaRS-linked CMT subtypes have begun to emerge, providing insights into the nonenzymatic functions of aaRSs and the pathogenesis of aaRS-linked CMT to guide therapeutic development to treat this disease.

Keywords: aminoacyl tRNA synthetase; animal model; drug development; genetic disease; neurodegenerative disease; pathogenesis; protein structure; protein synthesis; transfer RNA (tRNA); translation.

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Conflict of interest statement

The authors declare that they have no conflicts of interest with the contents of this article

Figures

Figure 1.
Figure 1.
Human disease association of aminoacyl-tRNA synthetases. CMT is the first human disease linked to aaRSs through dominant mono-allelic mutations. So far, only a selective set of aaRSs, including the dual-localized GARS and the cytosolic YARS, AARS, MARS, HARS, and WARS, have been linked to CMT (green). In contrast, recessive bi-allelic mutations in all mitochondrial aaRSs (orange) and the vast majority of cytosolic aaRSs (purple) have been linked to severe multisystem disorders. The mitochondrial aaRSs are designated with a “2” suffix to the symbol of the genes.
Figure 2.
Figure 2.
Prevalent characteristics of CMT-linked aaRSs. Prevalence rate is calculated as a ratio between the number of CMT-linked aaRSs and the total number of aaRSs within a certain category. Class I aaRSs include VARS, IARS, LARS, MARS, CARS, RARS, EARS, QARS, YARS, and WARS, and class II includes SARS, TARS, PARS, GARS, HARS, AARS, DARS, NARS, KARS, and FARS. The monomeric aaRSs are class I aaRSs except for YARS and WARS, which are dimers. Class II aaRSs are dimeric. FARS are tetrameric, which can be considered as a dimer of dimer. The MSC contains IARS, LARS, MARS, RARS, QARS KARS, DARS, EPRS/GluProRS, and three nonenzymatic factors. The WHEP domain–containing aaRSs include GARS, HARS, WARS, MARS, and EPRS.
Figure 3.
Figure 3.
Distribution of CMT-linked mutations in aaRSs. For GlyRS, the mutations are numbered according to the cytosolic form of the human protein and with the 54-amino acid mitochondrial targeting sequence omitted. The net increase of positive or negative charge(s) due to a CMT-associated mutation is indicated by “+” or “−” signs.
Figure 4.
Figure 4.
Genetic experiments used to clarify whether CMT2D is caused by a gain- or loss-of-function mechanism in mouse and fly models. CMT-like neuropathy phenotypes cannot be rescued by overexpressing WT GlyRS, suggesting toxic gain-of-function effects by the mutations as the cause of CMT2D. In contrast, phenotypes beyond CMT2D and caused by recessive bi-allelic mutations can be rescued by the WT GlyRS overexpression, suggesting some mutations do have loss-of-function properties, although they are not the cause of CMT.
Figure 5.
Figure 5.
Distribution of CMT-linked mutation sites in relationship to the dimer interface of aaRSs. A, GlyRS; B, TyrRS; C, HisRS; D, TrpRS; E, AlaRS. For clarity, aaRS dimers are shown in ribbon representation for one subunit and in space-filling model for the second subunit. CMT mutation sites directly located at the dimerization interface are colored in red; CMT mutation sites near but not immediately at the dimerization interface are labeled in green; CMT mutation sites far away from the dimerization interface are colored in dark blue. CMT-linked residues from the space-filling subunits are shown in italic type with ′. The crystal structures of human GlyRS (A), TyrRS (B) (without the C-terminal EMAP-II domain), and TrpRS (D) dimers are provided by PDB entries 2PME, 1N3L, and 1R6T, respectively. The structure of human HisRS dimer (C) is obtained by re-processing the deposited data of PDB 4X5O to reveal the WHEP domain (B. Kuhle, personal communication). The full-length human AlaRS dimer (E) is modeled based on PDB entries 3WQY, 5KNN, and 5T5S. The AlaRS editing domain from Archaeoglobus fulgidus (PDB 3WQY) was docked onto human AlaRS catalytic domain (PDB 5KNN) by superimposing the catalytic domains (RMSD 1.903 Å). Human C-Ala domain (PDB 5T5S) was further docked onto the model by following the domain arrangement of human AlaRS based on SAXS analysis in solution (10). The crystal structure of human C-Ala dimer (PDB 5T5S) provided the dimer interface.
Figure 6.
Figure 6.
Distribution of CMT-linked mutation sites in relationship to tRNA-binding sites on aaRSs. A dimeric aaRS is shown for GlyRS (A), TyrRS (B), HisRS (C), and TrpRS (D) because the dimer form is required to provide the complete binding sites for a single tRNA and is necessary for catalysis. In contrast, monomeric AlaRS (E) and MetRS (F) are sufficient for tRNA aminoacylation. In the dimeric cases, one subunit of the dimer is in ribbon representation, and the other subunit is in a space-filling model. CMT mutation sites are indicated as orange-red spheres. Mutations from surface presentation subunits are labeled in italic type with ′. A, human GlyRS/tRNAGly complex (PDB 5E6M). Insertion III (residues 423–518) was modeled by superimposing PDB 5E6M with another human GlyRS/tRNAGly structure (PDB 4QEI) with an RMSD of 0.803 Å, which indicates high accuracy of the structure model. B, human TyrRS/tRNATyr complex model. The complex was modeled by superimposing archaeal TyrRS/tRNATyr complex (PDB 1J1U) with human TyrRS catalytic and anticodon domains (PDB 1N3L) with an RMSD of 1.833 Å. In this model, two 3′-nucleotides of the tRNA are missing. C, human HisRS/tRNAHis complex model. The complex was modeled by superimposing the Thermos thermophilus HisRS/tRNAHis complex (PDB 4RDX) with human HisRS structure (PDB 4X5O), with an RMSD of 3.815 Å. Although the large RMSD indicates potential inaccuracy of the model, the tRNA fits well on the structure of human HisRS. D, human TrpRS/tRNATrp complex (PDB 2DR2). The WHEP domain was docked in by superimposing the complex with human TrpRS structure (PDB 1R6T) with a small RMSD of 0.6 Å. E, human AlaRS/tRNAAla complex model. The AlaRS and tRNAAla complex from A. fulgidus (PDB ID: 3WQY) was superimposed with the human AlaRS catalytic domain (PDB 5KNN) through the catalytic domains (RMSD 1.903 Å). Human C-Ala domain (PDB 5T5S) was further docked onto the model by following the domain arrangement of human AlaRS based on SAXS analysis in solution (10). The distances from the CMT mutation sites in C-Ala to tRNA may not be reliable, as the C-Ala domain may undergo structural re-arrangement upon tRNA binding. F, human MetRS/tRNAMet complex model. The Aquifex aeolicus MetRS/tRNAMet complex (PDB 2CSX) was superimposed with a truncated human MetRS structure (PDB 5GL7) with an RMSD of 1.67 Å.
Figure 7.
Figure 7.
Solution-based structural analyses reveal conformational opening induced by CMT-causing mutations to engender aberrant interactions. A, six different CMT2D mutations induce conformational change of GlyRS that opens consensus areas that overlap with the dimerization interface. B, three different DI-CMTC mutations open up a same area in TyrRS. The neomorphic surfaces are likely to be responsible for aberrant interactions made by the mutant aaRSs as illustrated.
Figure 8.
Figure 8.
Multifactorial and multicompartmental pathogenic mechanisms proposed for aaRS-linked CMT. In the nucleus, TyrRSCMT aberrantly interacts with the TRIM28/HDAC1 complex to overactivate transcriptional factor E2F1, which is normally suppressed in neurons.4 In the cytosol, TyrRSCMT and GlyRSCMT repress protein translation in motor and sensory neurons through an unknown mechanism independent of tRNA aminoacylation (41). The dual-localized GlyRSCMT also inhibits translation in mitochondria in mice and patient-induced neuronal progenitor cells (35). GlyRSCMT aberrantly interacts with HDAC6, leading to hypo-acetylation of α-tubulin and axonal transport deficits (96, 97). Extracellularly, secreted GlyRSCMT competes with VEGF to interact with the cell-surface receptor Nrp1 on motor neuron, interfering with the neurotrophic signaling of VEGF (76). Secreted GlyRSCMT was also detected at the motor neuron terminal to compete with Sema2a for binding to the cell-surface receptor plexin B in a fly-CMT model (93). GlyRSCMT also aberrantly interacts with the cell-surface receptor TrkA/B/C in mice to cause developmental imbalance of sensory neurons (95).
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References

    1. Woese C. R., Olsen G. J., Ibba M., and Söll D. (2000) Aminoacyl-tRNA synthetases, the genetic code, and the evolutionary process. Microbiol. Mol. Biol. Rev. 64, 202–236 10.1128/MMBR.64.1.202-236.2000 - DOI - PMC - PubMed
    1. Guo M., and Schimmel P. (2013) Essential nontranslational functions of tRNA synthetases. Nat. Chem. Biol. 9, 145–153 10.1038/nchembio.1158 - DOI - PMC - PubMed
    1. Yao P., and Fox P. L. (2013) Aminoacyl-tRNA synthetases in medicine and disease. EMBO Mol. Med. 5, 332–343 10.1002/emmm.201100626 - DOI - PMC - PubMed
    1. Kim S., You S., and Hwang D. (2011) Aminoacyl-tRNA synthetases and tumorigenesis: more than housekeeping. Nat. Rev. Cancer 11, 708–718 10.1038/nrc3124 - DOI - PubMed
    1. Alexandrova J., Paulus C., Rudinger-Thirion J., Jossinet F., and Frugier M. (2015) Elaborate uORF/IRES features control expression and localization of human glycyl-tRNA synthetase. RNA Biol. 12, 1301–1313 10.1080/15476286.2015.1086866 - DOI - PMC - PubMed

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