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Nature子刊:上海交大发表最新成果

摘要 : 上海交大和耶鲁大学的研究团队通过深入研究,揭示了MEKK3- CCM2复合体的结构和功能。这一成果发表在八月三日的Nature Communications杂志上,文章的通讯作者是上海交大的苏冰(Bing Su)教授和耶鲁大学的Titus J. Boggon。

 脑海绵状血管瘤(CCM)是发生于中枢神经系统的常见血管畸形,可导致多种神经性损伤,引起出血性中风、癫痫等症状。人们发现这种疾病与三个致病基因有关,它们编码的蛋白分别是CCM1、CCM2和CCM3。这三种蛋白都是接头蛋白,能够和多种配体相互作用,参与了多种生物学过程。理解CCM蛋白与其他蛋白的互作,有助于揭示脑海绵状血管瘤的发病机理。

家族性脑海绵状血管畸形与CCM2缺陷有关,而CCM2能够与蛋白激酶MEKK3相互作用。已知MEKK3对于小鼠胚胎的血管生成非常重要,但人们并不清楚MEKK3与CCM2互作的分子基础和具体功能。

上海交大和耶鲁大学的研究团队通过深入研究,揭示了MEKK3- CCM2复合体的结构和功能。这一成果发表在八月三日的Nature Communications杂志上,文章的通讯作者是上海交大的苏冰(Bing Su)教授和耶鲁大学的Titus J. Boggon。

研究显示,Mekk3在胚胎血管发育中起到了关键性作用。在新生小鼠中敲除内皮Mekk3,会引起颅内出血和大脑血管渗漏,最终导致小鼠死亡。研究人员还获得了MEKK3- CCM2复合体的2.35 Å晶体结构,发现CCM2的HHD结构域(harmonin homology domain)与MEKK3的N端直接相互作用。

研究指出,维持神经血管的完整性需要MEKK3- CCM2介导的信号调控。而CCM2缺陷会通过这一机制引发脑海绵状血管瘤。

推荐原文:Structure and vascular function of MEKK3–cerebral cavernous malformations 2 complex

Cerebral cavernous malformations 2 (CCM2) loss is associated with the familial form of CCM disease. The protein kinase MEKK3 (MAP3K3) is essential for embryonic angiogenesis in mice and interacts physically with CCM2, but how this interaction is mediated and its relevance to cerebral vasculature are unknown. Here we report that Mekk3 plays an intrinsic role in embryonic vascular development. Inducible endothelial Mekk3 knockout in neonatal mice is lethal due to multiple intracranial haemorrhages and brain blood vessels leakage. We discover direct interaction between CCM2 harmonin homology domain (HHD) and the N terminus of MEKK3, and determine a 2.35 Å cocrystal structure. We find Mekk3 deficiency impairs neurovascular integrity, which is partially dependent on Rho–ROCK signalling, and that disruption of MEKK3:CCM2 interaction leads to similar neurovascular leakage. We conclude that CCM2:MEKK3-mediated regulation of Rho signalling is required for maintenance of neurovascular integrity, unravelling a mechanism by whichCCM2 loss leads to disease.

来源: Nature Communications 浏览次数:0

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