Investigating the purpose of prelamin A processing
Investigating the purpose of prelamin A processing
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DOI：
10.4161/nucl.2.1.13723
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发表时间：
2011-01-01
期刊：
影响因子：
3.7
通讯作者：
Fong, Loren G.
中科院分区：
文献类型：
--
作者：
Davies, Brandon S. J.;Coffinier, Catherine;Fong, Loren G.
LMNA在体细胞中产生两种主要的蛋白质产物，层蛋白C和前层蛋白A。成熟的层蛋白A由前层蛋白A通过四个翻译后加工步骤产生--羧基半胱氨酸的法尼化，蛋白质的最后三个氨基酸的释放，法尼基半胱氨酸的甲基化，以及蛋白质的羧基末端15个氨基酸的内蛋白分解释放(包括法尼基半胱氨酸甲酯)。尽管前层蛋白A的翻译后加工在脊椎动物进化中是保守的，但其生理意义仍不清楚。在这里，我们回顾了最近的研究，在这些研究中，我们用LmNA敲入小鼠来研究Prelamin A的处理，这些小鼠只产生Prelamin A(Lmna(PLao))、成熟层蛋白A(Lmna(LAO))或非法尼化Prelamin A(Lmna(NPLao))。我们发现，层蛋白C的合成在实验室小鼠中是可有可无的，直接产生成熟的层蛋白A(完全绕过所有前层蛋白A的处理)在小鼠中不会导致可识别的病理，而独家产生非法尼化的前层蛋白A会导致心肌病。
Lmna yields two major protein products in somatic cells, lamin C and prelamin A. Mature lamin A is produced from prelamin A by four posttranslational processing steps-farnesylation of a carboxyl-terminal cysteine, release of the last three amino acids of the protein, methylation of the farnesylcysteine, and the endoproteolytic release of the carboxyl-terminal 15 amino acids of the protein (including the farnesylcysteine methyl ester). Although the posttranslational processing of prelamin A has been conserved in vertebrate evolution, its physiologic significance remains unclear. Here we review recent studies in which we investigated prelamin A processing with Lmna knock-in mice that produce exclusively prelamin A (Lmna(PLAO)), mature lamin A (Lmna(LAO)) or nonfarnesylated prelamin A (Lmna(nPLAO)). We found that the synthesis of lamin C is dispensable in laboratory mice, that the direct production of mature lamin A (completely bypassing all prelamin A processing) causes no discernable pathology in mice, and that exclusive production of nonfarnesylated prelamin A leads to cardiomyopathy.