Centre for Systems Biology, Samuel Lunenfeld Research Institute at Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
J Biol Chem. 2011 Jul 15;286(28):25056-64. doi: 10.1074/jbc.M110.213777. Epub 2011 May 11.
CCM3 mutations give rise to cerebral cavernous malformations (CCMs) of the vasculature through a mechanism that remains unclear. Interaction of CCM3 with the germinal center kinase III (GCKIII) subfamily of Sterile 20 protein kinases, MST4, STK24, and STK25, has been implicated in cardiovascular development in the zebrafish, raising the possibility that dysregulated GCKIII function may contribute to the etiology of CCM disease. Here, we show that the amino-terminal region of CCM3 is necessary and sufficient to bind directly to the C-terminal tail region of GCKIII proteins. This same region of CCM3 was shown previously to mediate homodimerization through the formation of an interdigitated α-helical domain. Sequence conservation and binding studies suggest that CCM3 may preferentially heterodimerize with GCKIII proteins through a manner structurally analogous to that employed for CCM3 homodimerization.
CCM3 突变通过一种尚未明确的机制导致血管性脑静脉畸形（CCMs）。CCM3 与生殖中心激酶 III（GCKIII）亚家族的无菌 20 蛋白激酶、MST4、STK24 和 STK25 的相互作用，已被牵涉到斑马鱼的心血管发育中，这增加了失调的 GCKIII 功能可能导致 CCM 疾病病因的可能性。在这里，我们表明 CCM3 的氨基末端区域是直接结合 GCKIII 蛋白的 C 末端尾部区域所必需和充分的。先前已经表明，CCM3 的同一区域通过形成交错的α螺旋结构域介导同二聚体化。序列保守性和结合研究表明，CCM3 可能通过与 CCM3 同二聚化结构上类似的方式，优先与 GCKIII 蛋白形成异二聚体。
