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首页> 外文期刊>Journal of Molecular Biology >Mitochondrial aminoacyl-tRNA synthetase single-nucleotide polymorphisms that lead to defects in refolding but not aminoacylation.
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Mitochondrial aminoacyl-tRNA synthetase single-nucleotide polymorphisms that lead to defects in refolding but not aminoacylation.

机译：线粒体氨酰基-tRNA合成酶单核苷酸多态性导致重新折叠中的缺陷，但不会导致氨酰化。

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摘要

Defects in organellar translation are the underlying cause of a number of mitochondrial diseases, including diabetes, deafness, encephalopathy, and other mitochondrial myopathies. The most common causes of these diseases are mutations in mitochondria-encoded tRNAs. It has recently become apparent that mutations in nuclear-encoded components of the mitochondrial translation machinery, such as aminoacyl-tRNA synthetases (aaRSs), can also lead to disease. In some cases, mutations can be directly linked to losses in enzymatic activity; however, for many, their effect is unknown. To investigate how aaRS mutations impact function without changing enzymatic activity, we chose nonsynonymous single-nucleotide polymorphisms (nsSNPs) that encode residues distal from the active site of human mitochondrial phenylalanyl-tRNA synthetase. The phenylalanyl-tRNA synthetase variants S57C and N280S both displayed wild-type aminoacylation activity and stability with respect to their free energies of unfolding, but were less stable at low pH. Mitochondrial proteins undergo partial unfolding/refolding during import, and both S57C and N280S variants retained less activity than wild type after refolding, consistent with their reduced stability at low pH. To examine possible defects in protein folding in other aaRS nsSNPs, we compared the refolding of the human mitochondrial leucyl-tRNA synthetase variant H324Q to that of wild type. The H324Q variant had normal activity prior to unfolding, but displayed a refolding defect resulting in reduced aminoacylation compared to wild type after renaturation. These data show that nsSNPs can impact mitochondrial translation by changing a biophysical property of a protein (in this case refolding) without affecting the corresponding enzymatic activity.
机译：细胞器翻译的缺陷是许多线粒体疾病的根本原因，包括糖尿病，耳聋，脑病和其他线粒体肌病。这些疾病的最常见原因是线粒体编码的tRNA突变。最近很明显，线粒体翻译机制的核编码成分中的突变，例如氨酰基-tRNA合成酶（aaRSs），也可能导致疾病。在某些情况下，突变可以直接与酶活性的丧失联系在一起。但是，对于许多人来说，其作用尚不清楚。为了研究aaRS突变如何在不改变酶活性的情况下影响功能，我们选择了非同义的单核苷酸多态性（nsSNPs），其编码远离人类线粒体苯丙氨酰-tRNA合成酶活性位点的残基。苯丙氨酰-tRNA合成酶变体S57C和N280S均表现出野生型氨基酰化活性和相对于其展开自由能的稳定性，但在低pH下则较不稳定。线粒体蛋白在导入过程中会发生部分解折叠/折叠，并且S57C和N280S变体在折叠后保留的活性均低于野生型，这与它们在低pH下的稳定性降低有关。为了检查其他aaRS nsSNP中蛋白质折叠的可能缺陷，我们比较了人类线粒体亮氨酰-tRNA合成酶变体H324Q与野生型的重折叠。 H324Q变体在展开前具有正常活性，但显示出重折叠缺陷，与复性后的野生型相比，导致氨基酰化减少。这些数据表明，nsSNP可通过改变蛋白质的生物物理特性（在这种情况下为复性）来影响线粒体翻译，而不会影响相应的酶活性。

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