Structural Mechanism of CCM3 Heterodimerization with GCKIII Kinases

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. [Display omitted] ► Crystal structure of CCM3-MST4 heterodimeric complex ► Structural mechanism driving CCM3-GCKIII heterodimerization ► Conformational changes required for CCM3-GCKIII heterodimerization ► Synergistic effects of CCM3-MST4 complex on cell proliferation and migration CCM3 heterodimerizes with GCKIII in a manner structurally resembling the CCM3 homodimerization. Zhang et al. reveal the mechanism through which critical residues drive CCM3-GCKIII heterodimerization versus homodimerization. Conformational changes of CCM3 are required for its homodimeric assembly and disassembly.