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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Membrane association is a determinant for substrate recognition by PMT4 protein O-mannosyltransferases
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Membrane association is a determinant for substrate recognition by PMT4 protein O-mannosyltransferases

机译：膜缔合是PMT4蛋白O-甘露糖基转移酶对底物识别的决定性因素

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摘要

Protein O-mannosylation represents an evolutionarily conserved, essential posttranslational modification with immense impact on a variety of cellular processes. In humans, O-mannosylation defects result in Walker-Warburg syndrome, a severe recessive congenital muscular dystrophy associated with defects in neuronal migration that produce complex brain and eye abnormalities. In mouse and yeasts, loss of O-mannosylation causes lethality. Protein O-mannosyltransferases (PMTs) initiate the assembly of O-mannosyl glycans. The evolutionarily conserved PMT family is classified into PMT1, PMT2, and PMT4 subfamilies, which mannosylate distinct target proteins. In contrast to other types of glycosylation, signal sequences for O-mannosylation have not been identified to date. In the present study, we identified signals that determine PMT4-dependent O-mannosylation. Using specific model proteins, we demonstrate that in yeast Pmt4p mediates O-mannosylation of Ser/Thr-rich membrane-attached proteins. The nature of the membrane-anchoring sequence is nonrelevant, as long as it is flanked by a Ser/Thr-rich domain facing the endoplasmic reticulum lumen. Our work shows that, in contrast to several other types of glycosylation, PMT4 O-mannosylation signals are not just linear protein's primary structure sequences but rather are highly complex. Based on these findings, we performed in silico analyses of the Saccharomyces cerevisiae proteome and identified previously undescribed Pmt4p substrates. This tool for proteome-wide identification of O-mannosylated proteins is of general interest because several of these proteins are major players of a wide variety of cellular processes.
机译：蛋白质O-甘露糖基化代表了一种进化保守的，必不可少的翻译后修饰，对多种细胞过程产生了巨大影响。在人类中，O-甘露糖基化缺陷会导致Walker-Warburg综合征，这是一种严重的先天性隐性肌营养不良症，与神经元迁移缺陷有关，会导致复杂的大脑和眼睛异常。在小鼠和酵母中，O-甘露糖基化的丧失会导致致命性。蛋白质O-甘露糖基转移酶（PMT）启动O-甘露糖基聚糖的组装。进化保守的PMT家族分为PMT1，PMT2和PMT4子家族，它们使甘露糖基化不同的靶蛋白。与其他类型的糖基化相反，迄今尚未鉴定出用于O-甘露糖基化的信号序列。在本研究中，我们鉴定了确定PMT4依赖性O-甘露糖基化的信号。使用特定的模型蛋白，我们证明在酵母Pmt4p介导富含Ser / Thr的膜附着蛋白的O-甘露糖基化。膜锚定序列的性质无关紧要，只要其侧翼是面向内质网腔的富含Ser / Thr的结构域即可。我们的工作表明，与其他几种类型的糖基化相反，PMT4 O-甘露糖基化信号不仅是线性蛋白质的一级结构序列，而且非常复杂。基于这些发现，我们对啤酒酵母蛋白质组进行了计算机分析，并确定了以前未描述的Pmt4p底物。蛋白质组学范围内的O-甘露糖基化蛋白鉴定工具受到广泛关注，因为其中一些蛋白是多种细胞过程的主要参与者。

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