tRNA-sequestration as an underlying molecular mechanism of tyrosyl-tRNA synthetase-associated DI-CMTC pathology

tRNA 隔离作为酪氨酰-tRNA 合成酶相关 DI-CMTC 病理学的潜在分子机制

• 批准号: 519147084
• 负责人: Professorin Dr. Zoya Ignatova
• 金额: --
• 依托单位: Institut für Biochemie und Molekularbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/519147084?language=en
• 关键词: tRNA; sequestration; underlying; molecular; mechanism

Aminoacyl-tRNA-synthetases (aaRS) are pivotal for protein translation; they aminoacylate tRNAs with cognate amino acid. Heterozygous mutations in six distinct AARSs are connected to devastating dominantly inherited Charcot-Marie-Tooth (CMT) peripheral neuropathies, which is characterized by degeneration of peripheral motor and sensory axons, leading to progressive muscle weakness and wasting and sensory dysfunction. The underlying molecular mechanisms of different CMT forms and their tissue-specific effect remain poorly understood. We recently reported a novel mechanism underlying the CMT2D pathology linked to mutations in the glycyl-tRNA synthetase (GARS), a class II aaRS. The CMT-mutant forms of GARS tightly bind the cognate tRNAs and fail to release them, thus, depleting glycyl-tRNAGly for translation and consequently causing ribosome stalling at Gly codons. Heterozygous mutations in YARS are causal to DI-CMTC pathology. By analysing the kinetics of tRNA binding and release of CMT-mutant tyrosyl-tRNA-synthetase (YARS) variants in Drosophila and mouse CMT models (YarsE196K mice), combined with cell-wide analysis of translation speed and expression, we will determine the molecular mechanism of another class I aaRS associated with CMT pathologies. We expect that this multilayered approach will reveal insights into common and distinct mechanistic facets of mutations in class I and class II aaRSs with a causal link to CMT pathologies.

氨酰-tRNA-合成酶（阿尔斯）是蛋白质翻译的关键酶，它们用同源氨基酸氨酰化tRNA。六种不同AARS中的杂合突变与破坏性显性遗传性腓骨肌萎缩症（CMT）周围神经病变有关，其特征在于外周运动和感觉轴突的变性，导致进行性肌无力和消瘦以及感觉功能障碍。不同CMT形式及其组织特异性作用的潜在分子机制仍然知之甚少。我们最近报道了一种与甘氨酰-tRNA合成酶（加尔斯）（一种II类阿尔斯）突变相关的CMT 2D病理学基础的新机制。加尔斯的CMT突变形式紧密结合同源tRNA，并且不能释放它们，因此，耗尽用于翻译的甘氨酰-tRNAGly，并因此导致核糖体在Gly密码子处停滞。YARS中的杂合突变是DI-CMTC病理的原因。通过分析果蝇和小鼠CMT模型（YarsE 196 K小鼠）中CMT突变体酪氨酸-tRNA-合成酶（YARS）变体的tRNA结合和释放的动力学，结合翻译速度和表达的细胞范围分析，我们将确定与CMT病理学相关的另一种I类阿尔斯的分子机制。我们期望这种多层次的方法将揭示I类和II类aaRS突变的共同和不同的机制方面与CMT病理的因果关系。