The tRNA-induced conformational activation of human mitochondrial phenylalanyl-tRNA synthetase.
All class II aminoacyl-tRNA synthetases (aaRSs) are known to be active as functional homodimers, homotetramers, or heterotetramers. However, multimeric organization is not a prerequisite for phenylalanylation activity, as monomeric mitochondrial phenylalanyl-tRNA synthetase (PheRS) is also active. We herein report the structure, at 2.2 A resolution, of a human monomeric mitPheRS complexed with Phe-AMP. The smallest known aaRS, which is, in fact, 1/5 of a cytoplasmic analog, is a chimera of the catalytic module of the alpha and anticodon binding domain (ABD) of the bacterial beta subunit of (alphabeta)2 PheRS. We demonstrate that the ABD located at the C terminus of mitPheRS overlaps with the acceptor stem of phenylalanine transfer RNA (tRNAPhe) if the substrate is positioned in a manner similar to that seen in the binary Thermus thermophilus complex. Thus, formation of the PheRS-tRNAPhe complex in human mitochondria must be accompanied by considerable rearrangement (hinge-type rotation through approximately 160 degrees) of the ABD upon tRNA binding.
Klipcan
Liron
L
Department of Structural Biology, Weizmann Institute of Science, 76100 Rehovot, Israel.
Levin
Inna
I
Kessler
Naama
N
Moor
Nina
N
Finarov
Igal
I
Safro
Mark
M
D000249:Adenosine Monophosphate / Q000031:analogs & derivatives / Q000737:chemistry; D000595:Amino Acid Sequence; D000604:Amino Acyl-tRNA Synthetases / Q000737:chemistry; D004789:Enzyme Activation; D006801:Humans; D024101:Mitochondrial Proteins / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010652:Phenylalanine-tRNA Ligase / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012360:RNA, Transfer, Phe / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid
D024101:Mitochondrial Proteins; D012360:RNA, Transfer, Phe; D000249:Adenosine Monophosphate; C017620:phenylalanyl-5'-AMP; D000604:Amino Acyl-tRNA Synthetases; D010652:Phenylalanine-tRNA Ligase