期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 294, 期 14, 页码 5321-5339出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.REV118.002955
关键词
aminoacyl tRNA synthetase; animal model; drug development; genetic disease; neurodegenerative disease; transfer RNA (tRNA); protein synthesis; protein structure; pathogenesis; translation
资金
- National Institutes of Health [R01 GM088278]
- National Foundation for Cancer Research
Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes that catalyze the first reaction in protein biosynthesis, namely the charging of transfer RNAs (tRNAs) with their cognate amino acids. aaRSs have been increasingly implicated in dominantly and recessively inherited human diseases. The most common aaRS-associated monogenic disorder is the incurable neurodegenerative disease Charcot-Marie-Tooth neuropathy (CMT), caused by dominant mono-allelic mutations in aaRSs. With six currently known members (GlyRS, TyrRS, AlaRS, HisRS, TrpRS, and MetRS), aaRSs represent the largest protein family implicated in CMT etiology. After the initial discovery linking aaRSs to CMT, the field has progressed from understanding whether impaired tRNA charging is a critical component of this disease to elucidating the specific pathways affected by CMT-causing mutations in aaRSs. Although many aaRS CMT mutants result in loss of tRNA aminoacylation function, animal genetics studies demonstrated that dominant mutations in GlyRS cause CMT through toxic gain-of-function effects, which also may apply to other aaRS-linked CMT subtypes. The CMT-causing mechanism is likely to be multifactorial and involves multiple cellular compartments, including the nucleus and the extracellular space, where the normal WT enzymes also appear. Thus, the association of aaRSs with neuropathy is relevant to discoveries indicating that aaRSs also have nonenzymatic regulatory functions that coordinate protein synthesis with other biological processes. Through genetic, functional, and structural analyses, commonalities among different mutations and different aaRS-linked CMT subtypes have begun to emerge, providing insights into the nonenzymatic functions of aaRSs and the pathogenesis of aaRS-linked CMT to guide therapeutic development to treat this disease.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据