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Table 3 Potential defects identified using our mutational annotation pipeline in aaRSs

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

Disease aaRS/mutations Previous functional annotation for mutation Structural/functional feature potentially affected (category for mutational annotation)
Charcot-Marie-Tooth disorder (CMT) GRS (Ala111Val) No reported annotation Un-annotated (d)
GRS (Glu125Gly) No reported annotation Dimerization (c)
GRS (Pro152Leu) No reported annotation Dimerization (c)
GRS (Leu183Pro) Defective dimerization Dimerization (c)
GRS (Cys211Arg) No reported annotation Structural stability (b)
GRS (Pro288Lys) No reported annotation Dimerization (c)
GRS (Gly294Arg) Defective dimerization Structural stability (b)
GRS (Pro298Leu) No reported annotation Structural stability (b)
GRS (Ile334Phe) No reported annotation Dimerization (c)
GRS (His472Arg) No reported annotation Structural stability (b)
GRS (Asp554Asn) Enhanced dimerization Un-annotated (d)
GRS (Gly580Arg) Enhanced dimerization Structural stability (b)
GRS (Ser635Leu) Enhanced dimerization Inter-molecular interaction (c)
GRS (Gly652Ala) No reported annotation Inter-molecular interaction (c)
YRS (Gly41Arg) Impaired tyrosine activation ATP/amino-acid binding (a)
YRS (Glu196Lys) No reported annotation Structural stability (b)
ARS (Asn71Tyr) Impaired tRNA charging Structural stability (b)
ARS (Arg329His) Imparired tRNA charging Structural stability (b)
ARS (Glu778Ala) No reported annotation Un-annotated (d)
ARS (Asp893Asn) No reported annotation Un-annotated (d)
KRS (Leu133His) Decreased enzyme activity Structural stability (b)
KRS (Ile302Met) No reported annotation Inter-molecular interactions (c)
KRS (Thr623Ser) No reported annotation Un-annotated (d)
Infantile hepatopathy LRS (Lys82Arg) No reported annotation Un-annotated (d)
LRS (Tyr373Cys) No reported annotation Structural stability (b)
Type-2 diabetes LRS (His324Gln) No reported annotation Structural stability (b)
Perrault syndrome, ovarian failure and hearing loss LRS (Thr522Asn) Decreased enzyme activity Structural stability (b)
LRS (Thr629Met) No reported annotation Structural stability (b)
HRS (Leu200Val) Decrease enzyme activity Structural stability (b)
HRS (Val368Leu) Decreased enzyme activity Structural stability (b)
Myopathy, lactic acidosis, and sideroblastic anemia (MLASA) YRS (Gly46Asp) Translational defects Inter-molecular interactions (c)
YRS (Phe52Leu) Abnormal enzyme kinetics Inter-molecular interactions (c)
HUPRA syndrome SRS (Asp390Gly) Decreased enzyme activity Structural stability (b)
SRS (Arg402His) No reported annotation Structural stability (b)
Infantile cardiomyopathies ARS (Leu155Arg) No reported annotation Un-annotated (d)
ARS (Arg592Trp) No reported annotation Un-annotated (d)
Ponto cerebellar hypoplasia RRS (Ile9Val) No reported annotation Un-annotated (d)
RRS (Gln12Arg) No reported annotation Un-annotated (d)
RRS (Trp241Arg) No reported annotation Structural stability (b)
RRS (Arg245Gln) No reported annotation Structural stability (b)
RRS (Arg469His) No reported annotation tRNA binding (a)
Leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate (LBSL) ERS (Arg55His) No reported annotation Structural stability (b)
ERS (Glu96Lys) No reported annotation Inter-molecular interactions (c)
ERS (Arg107His) No reported annotation Inter-molecular interactions (c)
ERS (Arg108Trp) No reported annotation Inter-molecular interactions (c)
ERS (Gly110Ser) No reported annotation Inter-molecular interactions (c)
ERS (Lys167Tyr) No reported annotation Un-annotated (d)
ERS (Arg168Gly) No reported annotation Un-annotated (d)
ERS (Gly204Ser) No reported annotation Inter-molecular interactions (c)
ERS (Gly224Ser) No reported annotation Inter-molecular interactions (c)
ERS (Gly317Cys) No reported annotation tRNA binding (a)
ERS (Arg516Gln) No reported annotation Structural stability (b)
DRS (Ser45Gly) No reported annotation Dimerization (c)
DRS (Cys152Phe) Defective dimerization Dimerization (c)
DRS (Arg179His) No reported annotation Inter-molecular interactions (c)
DRS (Leu239Pro) No reported annotation Un-annotated (d)
DRS (Arg263Gln) Defective dimerization Dimerization (c)
DRS (Leu613Phe) No reported annotation tRNA binding (a)
DRS (Leu626Gln) Decrease enzyme activity Inter-molecular interactions (c)
DRS (Leu626Val) No reported annotation Inter-molecular interactions (c)
Fatal infantile Alpers encephalopathy, mitochondrial myopathies FRS (Tyr144Cys) Defective tRNA binding Un-annotated (d)
FRS (Ile329Thr) Impaired stability/decreased ATP binding Structural stability (b)
FRS (Asp391Val) Impaired stability/decreased Phe binding Inter-molecular interactions (c)
  1. Mutation are annotated under four categories: (a) those likely to abrogate or disturb ligand or tRNA binding due to direct contacts with substrates/products, (b) those that are part of aaRS structural core and where mutation may directly affect enzyme folding/stability, (c) those that occur at protein surfaces which will end up being interfaces during assembly of oligomers (like dimeric interfaces), and (d) those that do not fall into any of the above and therefore where further experimentation may provide a mechanistic basis for mutational effects.