title: Structural mechanism of CCM3 heterodimerization with GCKIII kinases.
abstract: 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 flip over 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.
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhang
authors.forename: Liang
authors.initials: L
authors.lastname: Dong
authors.forename: Zhubing
authors.initials: Z
authors.lastname: Shi
authors.forename: Shi
authors.initials: S
authors.lastname: Jiao
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Wenqing
authors.initials: W
authors.lastname: Zhang
authors.forename: Guoguang
authors.initials: G
authors.lastname: Liu
authors.forename: Cuicui
authors.initials: C
authors.lastname: Chen
authors.forename: Miao
authors.initials: M
authors.lastname: Feng
authors.forename: Qian
authors.initials: Q
authors.lastname: Hao
authors.forename: Wenjia
authors.initials: W
authors.lastname: Wang
authors.forename: Mengxin
authors.initials: M
authors.lastname: Yin
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Zhaocai
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019281:Dimerization; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000099317:Hippo Kinases
chemical_list: D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; C495390:PDCD10 protein, human; C109163:STK24 protein, human; D000099317:Hippo Kinases; C430908:STK26 protein, human; C530660:STK25 protein, human