Structure and vascular function of MEKK3-cerebral cavernous malformations 2 complex.
Nat Commun
; 6: 7937, 2015 Aug 03.
Article
em En
| MEDLINE
| ID: mdl-26235885
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 MEKK3CCM2 interaction leads to similar neurovascular leakage. We conclude that CCM2MEKK3-mediated regulation of Rho signalling is required for maintenance of neurovascular integrity, unravelling a mechanism by which CCM2 loss leads to disease.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Vasos Sanguíneos
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Circulação Cerebrovascular
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Neovascularização Fisiológica
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Hemorragias Intracranianas
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MAP Quinase Quinase Quinase 3
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Proteínas dos Microfilamentos
Limite:
Animals
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article