Single nucleotide polymorphisms (SNPs) in RNF213, which encodes a 591kDa protein with AAA+ ATPase and RING E3 domains, are associated with a rare, autosomal dominant cerebrovascular disorder, Moyamoya disease (MMD). MMD-associated SNPs primarily localize to the C-terminal region of RNF213, and some affect conserved residues in the RING domain. Although the autosomal dominant inheritance of MMD could most easily be explained by RNF213 gain-of-function, the type of ubiquitylation catalyzed by RNF213 and the effects of MMD-associated SNPs on its E3-ligase activity have remained unclear. We found that the RING domain of RNF213 uses the E2-conjugating enzyme UBE2D2 to catalyze predominantly K6-dependent poly-ubiquitination events comprising a mixture of typical and atypical ubiquitin linkages. MMD-associated SNPs encode proteins with decreased E3-ligase activity and the most frequent MMD allele, RNF213R4810K, is a dominant negative mutant that decreases ubiquitylation globally. By contrast, MMD-associated RNF213 SNPs do not affect ATPase activity. We propose that decreased RNF213 E3-ligase activity is central to MMD pathogenesis.

中文翻译：

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与Moyamoya病相关的RNF213等位基因编码在全球范围内损害泛素化的显性负等位基因

RNF213中的单核苷酸多态性（SNP）编码具有AAA + ATPase和RING E3域的591kDa蛋白，与一种罕见的常染色体显性脑血管疾病Moyamoya病（MMD）相关。与MMD相关的SNP主要位于RNF213的C端区域，并且一些影响RING域中的保守残基。尽管可以通过RNF213功能获得最容易地解释MMD的常染色体显性遗传，但是RNF213催化的泛素化类型以及与MMD相关的SNP对其E3-连接酶活性的影响仍不清楚。我们发现RNF213的RING域使用E2缀合酶UBE2D2来催化主要是K6依赖性的多泛素化事件，该事件包括典型的和非典型的泛素键合。与MMD相关的SNP编码的E3连接酶活性降低的蛋白质，而最常见的MMD等位基因RNF213R4810K是占主导地位的负突变体，可在全球范围内降低泛素化。相反，与MMD相关的RNF213 SNP不影响ATPase活性。我们提出降低的RNF213 E3-连接酶活性是MMD发病机制的核心。