4Y5O: Ccm2 Hhd In Complex With Mekk3 Npb1

Citation:
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 A 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.
PDB ID: 4Y5ODownload
MMDB ID: 130540
PDB Deposition Date: 2015/2/11
Updated in MMDB: 2017/09
Experimental Method:
x-ray diffraction
Resolution: 2.35  Å
Source Organism:
Similar Structures:
Biological Unit for 4Y5O: dimeric; determined by author and by software (PISA)
Molecular Components in 4Y5O
Label Count Molecule
Proteins (2 molecules)
1
Malcavernin(Gene symbol: CCM2)
Molecule annotation
1
Mitogen-activated Protein Kinase Kinase Kinase 3(Gene symbol: MAP3K3)
Molecule annotation
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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