4Y5O

CCM2 HHD in complex with MEKK3 NPB1

4Y5O の概要

• エントリーDOI: 10.2210/pdb4y5o/pdb
• 分子名称: Malcavernin, Mitogen-activated protein kinase kinase kinase 3 (3 entities in total)
• 機能のキーワード: complex, kinase, scaffold, transferase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 25843.24

構造登録者

Fisher, O.S.,Boggon, T.J. (登録日: 2015-02-11, 公開日: 2015-07-01, 最終更新日: 2023-09-27)

主引用文献

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

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: 26235885
DOI: 10.1038/ncomms8937

実験手法

X-RAY DIFFRACTION (2.35 Å)