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

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...

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Autores principales: Draheim, Kyle M., Li, Xiaofeng, Zhang, Rong, Fisher, Oriana S., Villari, Giulia, Boggon, Titus J., Calderwood, David A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4384732/
https://www.ncbi.nlm.nih.gov/pubmed/25825518
http://dx.doi.org/10.1083/jcb.201407129
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author Draheim, Kyle M.
Li, Xiaofeng
Zhang, Rong
Fisher, Oriana S.
Villari, Giulia
Boggon, Titus J.
Calderwood, David A.
author_facet Draheim, Kyle M.
Li, Xiaofeng
Zhang, Rong
Fisher, Oriana S.
Villari, Giulia
Boggon, Titus J.
Calderwood, David A.
author_sort Draheim, Kyle M.
collection PubMed
description 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.
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spelling pubmed-43847322015-09-30 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. J Cell Biol Research Articles 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. The Rockefeller University Press 2015-03-30 /pmc/articles/PMC4384732/ /pubmed/25825518 http://dx.doi.org/10.1083/jcb.201407129 Text en © 2015 Draheim et al. https://creativecommons.org/licenses/by-nc-sa/3.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ (https://creativecommons.org/licenses/by-nc-sa/3.0/) ).
spellingShingle Research Articles
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
title CCM2–CCM3 interaction stabilizes their protein expression and permits endothelial network formation
title_full CCM2–CCM3 interaction stabilizes their protein expression and permits endothelial network formation
title_fullStr CCM2–CCM3 interaction stabilizes their protein expression and permits endothelial network formation
title_full_unstemmed CCM2–CCM3 interaction stabilizes their protein expression and permits endothelial network formation
title_short CCM2–CCM3 interaction stabilizes their protein expression and permits endothelial network formation
title_sort ccm2–ccm3 interaction stabilizes their protein expression and permits endothelial network formation
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4384732/
https://www.ncbi.nlm.nih.gov/pubmed/25825518
http://dx.doi.org/10.1083/jcb.201407129
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