Structural Mechanism of CCM3 Heterodimerization with GCKIII Kinases

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• 作者：Meng Zhang¹ ; ² ; Liang Dong¹ ; ² ; Zhubing Shi¹ ; ² ; Shi Jiao¹ ; ² ; Zhen Zhang¹ ; Wenqing Zhang¹ ; Guoguang Liu¹ ; Cuicui Chen¹ ; Miao Feng¹ ; Qian Hao¹ ; Wenjia Wang¹ ; Mengxin Yin¹ ; Yun Zhao¹ ; Lei Zhang¹ ; ^{rayzhang@sibcb.ac.cn} ; Zhaocai Zhou¹ ; ^{zczhou@sibcb.ac.cn}
• 刊名：Structure
• 出版年：2013
• 出版时间：2 April, 2013
• 年：2013
• 卷：21
• 期：4
• 页码：680-688
• 全文大小：1613 K

文摘

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Summary

Mutation of CCM3 causes cerebral cavernous malformations of the vasculature, leading to focal neurological deficits, seizures, and hemorrhagic stroke. CCM3 can heterodimerize with GCKIII kinases (MST3, MST4, and STK25) to regulate cardiovascular development. Here, we provide direct experimental evidence to prove that CCM3 heterodimerizes with GCKIII in a manner structurally resembling the CCM3 homodimerization. Structural comparison revealed the mechanism and critical residues that drive CCM3-GCKIII heterodimerization versus homodimerization. A flexible linker was identified for CCM3, which mediates a large-scale conformational rotation of the FAT domain relative to the dimerization domain. The conformational flipover of FAT domain removes steric locking in the CCM3 homodimer and allows its disassembly and subsequent heterodimerization with GCKIII. CCM3 forms a stable complex with MST4 in?vivo to promote cell proliferation and migration synergistically in a manner dependent on MST4 kinase activity. Collectively, our work offers a structural basis for further functional study.