Evolutionary and structural annotation of disease-associated mutations in human aminoacyl-tRNA synthetases

Abstract

BackgroundMutation(s) in proteins are a natural byproduct of evolution but can also cause serious diseases. Aminoacyl-tRNA synthetases (aaRSs) are indispensable components of all cellular protein translational machineries, and in humans they drive translation in both cytoplasm and mitochondria. Mutations in aaRSs have been implicated in a plethora of diseases including neurological conditions, metabolic disorders and cancer.ResultsWe have developed an algorithmic approach for genome-wide analyses of sequence substitutions that combines evolutionary, structural and functional information. This pipeline enabled us to super-annotate human aaRS mutations and analyze their linkage to health disorders. Our data suggest that in some but not all cases, aaRS mutations occur in functional and structural sectors where they can manifest their pathological effects by altering enzyme activity or causing structural instability. Further, mutations appear in both solvent exposed and buried regions of aaRSs indicating that these alterations could lead to dysfunctional enzymes resulting in abnormal protein translation routines by affecting inter-molecular interactions or by disruption of non-bonded interactions. Overall, the prevalence of mutations is much higher in mitochondrial aaRSs, and the two most often mutated aaRSs are mitochondrial glutamyl-tRNA synthetase and dual localized glycyl-tRNA synthetase. Out of 63 mutations annotated in this work, only 12 (~20%) were observed in regions that could directly affect aminoacylation activity via either binding to ATP/amino-acid, tRNA or by involvement in dimerization. Mutations in structural cores or at potential biomolecular interfaces account for ~55% mutations while remaining mutations (~25%) remain structurally un-annotated.ConclusionThis work provides a comprehensive structural framework within which most defective human aaRSs have been structurally analyzed. The methodology described here could be employed to annotate mutations in other protein families in a high-throughput manner.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-1063) contains supplementary material, which is available to authorized users.

FARS2 mutations presenting with pure spastic paraplegia and lesions of the dentate nuclei

“…To date, most mt‐aaRSs mutations involve a wide spectrum of central nervous system disorders with a broad range of phenotypes . For example, mutations in GARS cause peripheral neuropathy, MARS2 mutations have been associated with spastic ataxia with leukoencephalopathy, and DARS2 variants have been implicated in leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation …”

Evolutionary Limitation and Opportunities for Developing tRNA Synthetase Inhibitors with 5-Binding-Mode Classification

“…Human mitochondria have 17 mitochondria specific aaRSs, shares two cytoplasmic aaRS (GlyRS, and LysRS) [ 24 , 25 ], but lacks GlnRS, whose activity is compensated by GluRS and Glu-tRNA Gln amidotransferase in mitochondria [ 26 ]. Mutations or miss-regulation of these aaRSs are associated to several human diseases [ 27 , 28 , 29 ]. Mutations Lys81Thr and Arg751Gly in AlaRS reduce aminoacylation efficiency and are found in early infantile epileptic encephalopathy patients [ 30 ].…”

“…LysRS mutations Tyr145His and Asp349Asn are potential causes of autosomal recessive deafness [ 33 ]. Two LeuRS mutations outside of the active center Lys82Arg and Tyr373Cys are associated to infantile hepatopathies [ 28 , 34 ]. MetRS mutations Phe370Leu and Ile523Thr are found in infantile liver failure syndrome 2 patients [ 35 ].…”

Backbone Brackets and Arginine Tweezers delineate Class I and Class II aminoacyl tRNA synthetases

“…One contradicting theory is the coevolutionary theory of the 111 genetic code [15]. This theory suggests two main groups of amino acids based on the 112 connectedness of their biochemical pathways and that amino acid biosynthesis was the 113 dominant factor that shaped the genetic code [19]. Other authors suggested that both 114 classes evolved from unrelated ancestors and are of independent origin [23].…”

“…Furthermore, this mutation induces a larger contact area in the homo-dimer interface, 539 which stems partially from the anticodon binding domain [84]. Other mutations result 540 in a wider range of diseases and symptoms such as hearing loss, ovarian failure, or 541 cardiomyopathy [112,113]. Even for cellular processes unrelated to translation, aaRS 542 play a pivotal role, e.g.…”