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。

    已知CCM2通过与MEKK3(mitogen-activated protein kinase)相互作用对其信号进行负调控，或者在面临渗透压力时介导MEKK3信号的激活，这对于正常的心血管发育很重要。不过，人们此前还不了解CCM2-MEKK3互作的分子基础。

  
    中科院生物物理所的研究团队通过结构分析，揭示了CCM2和MEKK3之间的分子识别机制。这一成果发表在五月十四日的Structure杂志上，文章的通讯作者是中科院生物物理所的丁璟珒(Jingjin Ding)博士和王大成(Da-Cheng Wang)院士。

    王大成院士是我国著名的分子生物物理学家，长期从事蛋白质三维结构与功能及其分子改造研究，在蛋白激素、多肽生物毒素、动植物防御相关蛋白等领域取得突出的系统性创造性学术成就。2005年当选为中国科学院院士。

    研究人员获得了CCM2 C端部分(CCM2ct)的晶体结构，包含五螺旋结构域(CCM2cts)和后面的C端尾巴。他们发现，C端尾巴是一个单独的螺旋，与CCM2cts进行分子内互作，形成球形的六螺旋结构域。(延伸阅读：中科院院士Cell子刊发表新研究成果)

    生化研究表明，MEKK3的N端两亲螺旋(MEKK3-nhelix)是CCM2ct结合的基本结构元件。研究人员进一步分析了CCM2cts- MEKK3-nhelix复合体的晶体结构，发现它们之间的结合类似于CCM2ct 的分子内互作，MEKK3-nhelix就位于在分子内互作位点上。

    这项研究建立了一个结构框架，有助于进一步理解CCM2ct-MEKK3的分子识别机制。

    原文标题：Structural Insights into the Molecular Recognition between Cerebral Cavernous Malformation 2 and Mitogen-Activated Protein Kinase Kinase Kinase 3

    原文摘要：ABSTRACT Escherichia coli MutT hydrolyzes 8-oxo-dGTP to 8-oxo-dGMP, an event that can prevent the misincorporation of 8-oxoguanine opposite adenine in DNA. Of the several enzymes that recognize 8-oxoguanine, MutT exhibits high substrate specificity for 8-oxoguanine nucleotides; however, the structural basis for this specificity is unknown. The crystal structures of MutT in the apo and holo forms and in the binary and ternary forms complexed with the product 8-oxo-dGMP and 8-oxo-dGMP plus Mn(2+), respectively, were determined. MutT strictly recognizes the overall conformation of 8-oxo-dGMP through a number of hydrogen bonds. This recognition mode revealed that 8-oxoguanine nucleotides are discriminated from guanine nucleotides by not only the hydrogen bond between the N7-H and Odelta (N119) atoms but also by the syn glycosidic conformation that 8-oxoguanine nucleotides prefer. Nevertheless, these discrimination factors cannot by themselves explain the roughly 34,000-fold difference between the affinity of MutT for 8-oxo-dGMP and dGMP. When the binary complex of MutT with 8-oxo-dGMP is compared with the ligand-free form, ordering and considerable movement of the flexible loops surrounding 8-oxo-dGMP in the binary complex are observed. These results indicate that MutT specifically recognizes 8-oxoguanine nucleotides by the ligand-induced conformational change.