title: The insertion domain 1 of class IIA dimeric glycyl-tRNA synthetase is a rubredoxin-like zinc ribbon.
abstract: The insertion domain 1 (ID1) of class IIA dimeric glycyl-tRNA synthetase (α2GRS) is an appended domain in the core catalytic region of the enzyme. ID1 has been shown to play a role in tRNA aminoacylation, mediating interaction with the acceptor arm of tRNA and diadenosine tetraphosphate (Ap4A) synthesis. Mutations in α2GRS, including those in the ID1 region, have been implicated in distal hereditary motor neuropathy-V (dHMN-V) and Charcot-Marie-Tooth (CMT) disease. Through sequence and structure based evolutionary analysis, we show that ID1 of α2GRS is a rubredoxin-like zinc ribbon domain. The zinc-chelating cysteines of ID1 are well conserved in all archaeal versions of the enzyme and also in several eukaryotes, which most likely have acquired them via horizontal gene transfer from bacteria; but in all other eukaryotes, the zinc-chelating residues are not preserved. ID1 from bacteria display a selective preservation of zinc-binding residues, ranging from complete conservation to complete loss. The ID1 from different organisms harbor variable-sized non-conserved insertions between the two zinc-binding half-sites of the zinc ribbon. Three of the previously identified CMT-associated mutations in α2GRS, viz., human D146N, mouse C157R and human S211F, are located in the zinc ribbon region of ID1. Interestingly, human Asp146 which is implicated in the synthesis of Ap4A, a molecule known to act during neuronal transmission, has also been reported to be mutated in dHMN-V, suggesting a possible link between hereditary motor neuropathy and Ap4A synthesis.
authors.affiliation: CSIR-Institute of Microbial Technology, Sector 39A, Chandigarh, India.
authors.forename: Gurmeet
authors.initials: G
authors.lastname: Kaur
authors.affiliation: CSIR-Institute of Microbial Technology, Sector 39A, Chandigarh, India. Electronic address: krishna@imtech.res.in.
authors.forename: Srikrishna
authors.initials: S
authors.lastname: Subramanian
mesh_terms: D000595:Amino Acid Sequence; D017124:Conserved Sequence; D019143:Evolution, Molecular; D006032:Glycine-tRNA Ligase / Q000737:chemistry*; D006801:Humans; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary
chemical_list: D006032:Glycine-tRNA Ligase
keywords: Aminoacyl tRNA synthetase; Ap4A; Charcot–Marie–Tooth disease; Glycyl-tRNA synthetase; Hereditary motor neuropathy; Insertion domain 1; Zinc finger