Department of Molecular Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo 0316 Norway.
Nat Commun. 2012;3:1038. doi: 10.1038/ncomms2041.
Valosin-containing protein (VCP, also called p97) is an essential and highly conserved adenosine triphosphate-dependent chaperone implicated in a wide range of cellular processes in eukaryotes, and mild VCP mutations can cause severe neurodegenerative disease. Here we show that mammalian VCP is trimethylated on Lys315 in a variety of cell lines and tissues, and that the previously uncharacterized protein METTL21D (denoted here as VCP lysine methyltransferase, VCP-KMT) is the responsible enzyme. VCP methylation was abolished in three human VCP-KMT knockout cell lines generated with zinc-finger nucleases. Interestingly, VCP-KMT was recently reported to promote tumour metastasis, and indeed, VCP-KMT-deficient cells displayed reduced growth rate, migration and invasive potential. Finally, we present data indicating that VCP-KMT, calmodulin-lysine methyltransferase and eight uncharacterized proteins together constitute a novel human protein methyltransferase family. The present work provides new insights on protein methylation and its links to human disease.
包含缬氨酸的蛋白（VCP，也称为 p97）是一种必需的、高度保守的三磷酸腺苷依赖性伴侣，在真核生物的多种细胞过程中都有涉及，而轻度的 VCP 突变会导致严重的神经退行性疾病。在这里，我们表明哺乳动物 VCP 在多种细胞系和组织中 Lys315 上被三甲基化，而之前未被表征的蛋白 METTL21D（在这里表示为 VCP 赖氨酸甲基转移酶，VCP-KMT）是负责的酶。三种使用锌指核酸酶生成的人 VCP-KMT 敲除细胞系中，VCP 甲基化被消除。有趣的是，VCP-KMT 最近被报道可促进肿瘤转移，事实上，VCP-KMT 缺陷细胞的生长速度、迁移和侵袭能力降低。最后，我们提供的数据表明，VCP-KMT、钙调蛋白赖氨酸甲基转移酶和八个未被表征的蛋白一起构成了一个新的人类蛋白甲基转移酶家族。本工作为蛋白甲基化及其与人类疾病的关系提供了新的见解。
