7ea9
From Proteopedia
Crystal Structure of human lysyl-tRNA synthetase Y145H mutant
Structural highlights
Disease[SYK_HUMAN] Defects in KARS are the cause of Charcot-Marie-Tooth disease recessive intermediate type B (CMTRIB) [MIM:613641]; also called Charcot-Marie-Tooth neuropathy recessive intermediate B. CMTRIB is a form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Recessive intermediate forms of Charcot-Marie-Tooth disease are characterized by clinical and pathologic features intermediate between demyelinating and axonal peripheral neuropathies, and motor median nerve conduction velocities ranging from 25 to 45 m/sec.[1] Function[SYK_HUMAN] Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA. When secreted, acts as a signaling molecule that induces immune response through the activation of monocyte/macrophages. Catalyzes the synthesis of diadenosine oligophosphate (Ap4A), a signaling molecule involved in the activation of MITF transcriptional activity. Interacts with HIV-1 virus GAG protein, facilitating the selective packaging of tRNA(3)(Lys), the primer for reverse transcription initiation.[2] [3] Publication Abstract from PubMedAminoacyl-tRNA synthetases (AARSs) catalyze the ligation of amino acids to their cognate tRNAs and therefore play an essential role in protein biosynthesis in all living cells. The KARS gene in human encodes both cytosolic and mitochondrial lysyl-tRNA synthetase (LysRS). A recent study identified a missense mutation in KARS gene (c.517T > C) that caused autosomal recessive nonsyndromic hearing loss. This mutation led to a tyrosine to histidine (YH) substitution in both cytosolic and mitochondrial LysRS proteins, and decreased their aminoacylation activity to different levels. Here, we report the crystal structure of LysRS YH mutant at a resolution of 2.5 A. We found that the mutation did not interfere with the active center, nor did it cause any significant conformational changes in the protein. The loops involved in tetramer interface and tRNA anticodon binding site showed relatively bigger variations between the mutant and wild type proteins. Considering the differences between the cytosolic and mitochondrial tRNA(lys)s, we suggest that the mutation triggered subtle changes in the tRNA anticodon binding region, and the interferences were further amplified by the different D and T loops in mitochondrial tRNA(lys), and led to a complete loss of the aminoacylation of mitochondrial tRNA(lys). Structural analyses of a human lysyl-tRNA synthetase mutant associated with autosomal recessive nonsyndromic hearing impairment.,Wu S, Hei Z, Zheng L, Zhou J, Liu Z, Wang J, Fang P Biochem Biophys Res Commun. 2021 May 21;554:83-88. doi:, 10.1016/j.bbrc.2021.03.093. Epub 2021 Mar 27. PMID:33784510[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Human | Large Structures | Fang, P | Hei, Z | Liu, Z | Wang, J | Wu, S | Zheng, L | Zhou, J | Disease related mutant | Ligase | Lysr | Lysyl-trna synthetase
