CCM2-CCM3 interaction stabilizes their protein expression and permits endothelial network formation

Kyle M. Draheim, Xiaofeng Li, Rong Zhang, Oriana S. Fisher, Giulia Villari, Titus J. Boggon, David A. Calderwood

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Mutations in the essential adaptor proteins CCM2 or CCM3 lead to cerebral cavernous malformations (CCM), vascular lesions that most frequently occur in the brain and are strongly associated with hemorrhagic stroke, seizures, and other neurological disorders. CCM2 binds CCM3, but the molecular basis of this interaction, and its functional significance, have not been elucidated. Here, we used x-ray crystallography and structure-guided mutagenesis to show that an α-helical LD-like motif within CCM2 binds the highly conserved "HP1" pocket of the CCM3 focal adhesion targeting (FAT) homology domain. By knocking down CCM2 or CCM3 and rescuing with binding-deficient mutants, we establish that CCM2-CCM3 interactions protect CCM2 and CCM3 proteins from proteasomal degradation and show that both CCM2 and CCM3 are required for normal endothelial cell network formation. However, CCM3 expression in the absence of CCM2 is sufficient to support normal cell growth, revealing complex-independent roles for CCM3.

Original languageEnglish
Pages (from-to)987-1001
Number of pages15
JournalJournal of Cell Biology
Volume208
Issue number7
DOIs
Publication statusPublished - 2015

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Central Nervous System Cavernous Hemangioma
Crystallography
Focal Adhesions
Nervous System Diseases
Mutagenesis
Proteolysis
Blood Vessels
Seizures
Endothelial Cells
Stroke
X-Rays
Mutation
Brain
Growth
Proteins

ASJC Scopus subject areas

  • Cell Biology

Cite this

Draheim, K. M., Li, X., Zhang, R., Fisher, O. S., Villari, G., Boggon, T. J., & Calderwood, D. A. (2015). CCM2-CCM3 interaction stabilizes their protein expression and permits endothelial network formation. Journal of Cell Biology, 208(7), 987-1001. https://doi.org/10.1083/jcb.201407129

CCM2-CCM3 interaction stabilizes their protein expression and permits endothelial network formation. / Draheim, Kyle M.; Li, Xiaofeng; Zhang, Rong; Fisher, Oriana S.; Villari, Giulia; Boggon, Titus J.; Calderwood, David A.

In: Journal of Cell Biology, Vol. 208, No. 7, 2015, p. 987-1001.

Research output: Contribution to journalArticle

Draheim, KM, Li, X, Zhang, R, Fisher, OS, Villari, G, Boggon, TJ & Calderwood, DA 2015, 'CCM2-CCM3 interaction stabilizes their protein expression and permits endothelial network formation', Journal of Cell Biology, vol. 208, no. 7, pp. 987-1001. https://doi.org/10.1083/jcb.201407129
Draheim, Kyle M. ; Li, Xiaofeng ; Zhang, Rong ; Fisher, Oriana S. ; Villari, Giulia ; Boggon, Titus J. ; Calderwood, David A. / CCM2-CCM3 interaction stabilizes their protein expression and permits endothelial network formation. In: Journal of Cell Biology. 2015 ; Vol. 208, No. 7. pp. 987-1001.
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