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From Proteopedia
Crystal Structure of Human LysRS: P38/AIMP2 Complex II
Structural highlights
DiseaseSYK_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] FunctionSYK_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 PubMedMulti-aminoacyl-tRNA synthetase complex (MSC) is the second largest machinery for protein synthesis in human cells and also regulates multiple nontranslational functions through its components. Previous studies have shown that the MSC can respond to external signals by releasing its components to function outside it. The internal assembly is fundamental to MSC regulation. Here, using crystal structural analyses (at 1.88 A resolution) along with molecular modeling, gel filtration chromatography, and co-immunoprecipitation, we report that human lysyl-tRNA synthetase (LysRS) forms a tighter assembly with the scaffold protein aminoacyl-tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2) than previously observed. We found that two AIMP2 N-terminal peptides form an antiparallel scaffold and hold two LysRS dimers through four binding motifs and additional interactions. Of note, the four catalytic subunits of LysRS in the tightly assembled complex were all accessible for tRNA recognition. We further noted that two recently reported human disease-associated mutations conflict with this tighter assembly, cause LysRS release from the MSC, and inactivate the enzyme. These findings reveal a previously unknown dimension of MSC subcomplex assembly and suggest that the retractility of this complex may be critical for its physiological functions. Retractile lysyl-tRNA synthetase-AIMP2 assembly in the human multi-aminoacyl-tRNA synthetase complex.,Hei Z, Wu S, Liu Z, Wang J, Fang P J Biol Chem. 2019 Feb 7. pii: RA118.006356. doi: 10.1074/jbc.RA118.006356. PMID:30733335[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Homo sapiens | Large Structures | Fang P | Hei Z | Liu Z | Wang J
