4Y5O
CCM2 HHD in complex with MEKK3 NPB1
Summary for 4Y5O
| Entry DOI | 10.2210/pdb4y5o/pdb |
| Descriptor | Malcavernin, Mitogen-activated protein kinase kinase kinase 3 (3 entities in total) |
| Functional Keywords | complex, kinase, scaffold, transferase |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 25843.24 |
| Authors | Fisher, O.S.,Boggon, T.J. (deposition date: 2015-02-11, release date: 2015-07-01, Last modification date: 2023-09-27) |
| Primary citation | Fisher, O.S.,Deng, H.,Liu, D.,Zhang, Y.,Wei, R.,Deng, Y.,Zhang, F.,Louvi, A.,Turk, B.E.,Boggon, T.J.,Su, B. Structure and vascular function of MEKK3-cerebral cavernous malformations 2 complex. Nat Commun, 6:7937-7937, 2015 Cited by PubMed Abstract: Cerebral cavernous malformations 2 (CCM2) loss is associated with the familial form of CCM disease. The protein kinase MEKK3 (MAP3K3) is essential for embryonic angiogenesis in mice and interacts physically with CCM2, but how this interaction is mediated and its relevance to cerebral vasculature are unknown. Here we report that Mekk3 plays an intrinsic role in embryonic vascular development. Inducible endothelial Mekk3 knockout in neonatal mice is lethal due to multiple intracranial haemorrhages and brain blood vessels leakage. We discover direct interaction between CCM2 harmonin homology domain (HHD) and the N terminus of MEKK3, and determine a 2.35 Å cocrystal structure. We find Mekk3 deficiency impairs neurovascular integrity, which is partially dependent on Rho-ROCK signalling, and that disruption of MEKK3:CCM2 interaction leads to similar neurovascular leakage. We conclude that CCM2:MEKK3-mediated regulation of Rho signalling is required for maintenance of neurovascular integrity, unravelling a mechanism by which CCM2 loss leads to disease. PubMed: 26235885DOI: 10.1038/ncomms8937 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.35 Å) |
Structure validation
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