Insight into structural and bio-medical aspects of human mitochondrial
AaRSs are enzymes that aminoacylate tRNAs with their cognate amino acids. These proteins
play a crucial role in keeping the fidelity of the protein biosynthesis. In eukaryotes, protein
synthesis occurs not only in the cytoplasm, but also in different organelles, such as mitochondria
and chloroplasts. In the majority of organisms, mitochondrial aaRSs (mit-aaRSs) are encoded in
the nucleus and then post-translationally transported into the organelles Recent findings indicate
that at least 100 known human genetic diseases originate from mutations in the mitochondrial
Recently we solved the structure of human mitochondrial phenylalanyl-tRNA synthetase (mit-
PheRS). The PheRS is the enzyme responsible for specific incorporation of the phenylalanine
into protein polypeptide chain, catalyzing the phenylalanylation reaction. While the bacterial and
eukaryotic cytoplasmic PheRSs are functional ()2 heterodimers with a total length more than
2000 residues the mit-PheRS homolog is a 415 amino acid monomeric enzyme, and in fact is a
chimera of the catalytic module of the - and anticodon-binding domain (ABD) of the bacterial
-subunit of ()2 PheRS.
At least seven different point mutations in human mitochondrial tRNAPhe have been reported.
Particularly the G34A pathogenic mutation in human mitochondrial tRNAPhe is associated with
MERRF syndrome, a rare, serious muscular disorder caused by a defect in the genetic material
arising from the mitochondria. We intend to determine the 3D structure of human mit-PheRS and
its complexes with native and mutated tRNAs. Based on the structural knowledge we are
planning to modify mit-PheRSs to rescue the function of mutant tRNAs.
Levin I, Kessler N, Moor N, Klipcan L, Koc E, Templeton P, Spremulli L, Safro M. Purification,
crystallization and preliminary X-ray characterization of a human mitochondrial phenylalanyl-tRNA
synthetase. Acta Crystallogr Sect F Struct Biol Cryst Commun 2007, 63: 761-4.
Klipcan L, Levin I, Kessler N, Moor N, Finarov I, Safro M. The tRNA-induced conformational
activation of human mitochondrial phenylalanyl-tRNA synthetase. Structure 2008, 16: 1095-10.