Functional analyses of human and zebrafish 18-amino acid in-frame deletion pave the way for domain mapping of the cerebral cavernous malformation 3 protein

Voss, Katrin, Stahl, Sonja, Hogan, Benjamin M., Reinders, Joerg, Schleider, Elisa, Schulte-Merker, Stefan and Felbor, Ute (2009) Functional analyses of human and zebrafish 18-amino acid in-frame deletion pave the way for domain mapping of the cerebral cavernous malformation 3 protein. Human Mutation, 30 6: 1003-1011. doi:10.1002/humu.20996


Author Voss, Katrin
Stahl, Sonja
Hogan, Benjamin M.
Reinders, Joerg
Schleider, Elisa
Schulte-Merker, Stefan
Felbor, Ute
Title Functional analyses of human and zebrafish 18-amino acid in-frame deletion pave the way for domain mapping of the cerebral cavernous malformation 3 protein
Journal name Human Mutation   Check publisher's open access policy
ISSN 1059-7794
1098-1004
Publication date 2009
Year available 2009
Sub-type Article (original research)
DOI 10.1002/humu.20996
Open Access Status
Volume 30
Issue 6
Start page 1003
End page 1011
Total pages 9
Place of publication Hoboken, NJ United States
Publisher John Wiley and Sons, Inc.
Collection year 2009
Language eng
Subject 1311 Genetics
2716 Genetics (clinical)
Abstract Cerebral cavernous malformations (CCMs) may cause recurrent headaches, seizures, and hemorrhagic stroke and have been associated with loss-of-function mutations in CCM1/KRIT1, CCM2, and CCM3/programmed cell death 10 (PDCD10). The CCM3/PDCD10 amino acid sequence does not reveal significant homologies to protein domains with known structure. With the help of the only published human inframe deletion of the CCM3 gene (c.97-?-150+?del), CCM3:p.L33-K50del, we have identified the interaction domain of CCM3 with the oxidant stress response serine/threonine kinase 25 (STK25, YSK1, SOK1) and with the mammalian Ste20-like kinase 4 (MST4, MASK). Consistently, nano-liquid chromatography-tandem mass spectrometry (nano-LC-MS/MS) analyses revealed two STK25 phosphorylation sites at serine 39 and threonine 43. The corresponding in-frame deletion of zebrafish ccm3a, dccm3:p.L31-K48del, also resulted in impaired interaction with STK25 and MST4. In agreement with the observed redundant biochemical functionality of zebrafish ccm3a and its duplicate ccm3b, simultaneous inactivation of both genes resulted in a progressive cardiovascular phenotype in zebrafish indistinguishable from ccm1 and ccm2 mutants. The pronounced cardiovascular dilatations could be recapitulated by morpholino-induced in-frame skipping of the exon encoding the STK25 and MST4 binding site of zebrafish Ccm3a if Ccm3b was repressed in parallel. Using a novel zebrafish model of CCM, we could thus demonstrate that the newly mapped STK25 and MST4 interaction domain within the CCM3 protein plays a crucial role for vascular development in zebrafish.
Keyword Cerebral cavernous malformation
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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