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

•CCM2ct assembles into a global six-helix domain by intramolecular interaction•CCM2ct intramolecular interaction is weak•MEKK3-nhelix is the crucial structural element for CCM2ct binding•The binding of CCM2ct to MEKK3-nhelix resembles CCM2ct intramolecular interaction

SummaryCerebral cavernous malformation 2 (CCM2) functions as an adaptor protein implicated in various biological processes. By interacting with the mitogen-activated protein kinase MEKK3, CCM2 either mediates the activation of MEKK3 signaling in response to osmotic stress or negatively regulates MEKK3 signaling, which is important for normal cardiovascular development. However, the molecular basis governing CCM2-MEKK3 interaction is largely unknown. Here we report the crystal structure of the CCM2 C-terminal part (CCM2ct) containing both the five-helix domain (CCM2cts) and the following C-terminal tail. The end of the C-terminal tail forms an isolated helix, which interacts intramolecularly with CCM2cts. By biochemical studies we identified the N-terminal amphiphilic helix of MEKK3 (MEKK3-nhelix) as the essential structural element for CCM2ct binding. We further determined the crystal structure of CCM2cts-MEKK3-nhelix complex, in which MEKK3-nhelix binds to the same site of CCM2cts for CCM2ct intramolecular interaction. These findings build a structural framework for understanding CCM2ct-MEKK3 molecular recognition.

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