Dual-mode recognition of noncanonical tRNAsSer by seryl-tRNA synthetase in mammalian mitochondria

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Abstract
The secondary structures of metazoan mitochondrial (mt) tRNAsSer deviate markedly from the paradigm of the canonical cloverleaf structure; particularly, tRNASerGCU corresponding to the AG Y codon ( Y =U and C) is highly truncated and intrinsically missing the entire dihydrouridine arm. None of the mt serine isoacceptors possesses the elongated variable arm, which is the universal landmark for recognition by seryl‐tRNA synthetase (SerRS). Here, we report the crystal structure of mammalian mt SerRS from Bos taurus in complex with seryl adenylate at an atomic resolution of 1.65 Å. Coupling structural information with a tRNA‐docking model and the mutagenesis studies, we have unraveled the key elements that establish tRNA binding specificity, differ from all other known bacterial and eukaryotic systems, are the characteristic extensions in both extremities, as well as a few basic residues residing in the amino‐terminal helical arm of mt SerRS. Our data further uncover an unprecedented mechanism of a dual‐mode recognition employed to discriminate two distinct ‘bizarre’ mt tRNAsSer by alternative combination of interaction sites.