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Structural basis of the junctional anchorage of the cerebral cavernous malformations complex

The products of genes that cause cerebral cavernous malformations (CCM1/KRIT1, CCM2, and CCM3) physically interact. CCM1/KRIT1 links this complex to endothelial cell (EC) junctions and maintains junctional integrity in part by inhibiting RhoA. Heart of glass (HEG1), a transmembrane protein, associat...

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Detalles Bibliográficos
Autores principales: Gingras, Alexandre R., Liu, Jian J., Ginsberg, Mark H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3461514/
https://www.ncbi.nlm.nih.gov/pubmed/23007647
http://dx.doi.org/10.1083/jcb.201205109
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author Gingras, Alexandre R.
Liu, Jian J.
Ginsberg, Mark H.
author_facet Gingras, Alexandre R.
Liu, Jian J.
Ginsberg, Mark H.
author_sort Gingras, Alexandre R.
collection PubMed
description The products of genes that cause cerebral cavernous malformations (CCM1/KRIT1, CCM2, and CCM3) physically interact. CCM1/KRIT1 links this complex to endothelial cell (EC) junctions and maintains junctional integrity in part by inhibiting RhoA. Heart of glass (HEG1), a transmembrane protein, associates with KRIT1. In this paper, we show that the KRIT1 band 4.1, ezrin, radixin, and moesin (FERM) domain bound the HEG1 C terminus (K(d) = 1.2 µM) and solved the structure of this assembly. The KRIT1 F1 and F3 subdomain interface formed a hydrophobic groove that binds HEG1(Tyr(1,380)-Phe(1,381)), thus defining a new mode of FERM domain–membrane protein interaction. This structure enabled design of KRIT1(L717,721A), which exhibited a >100-fold reduction in HEG1 affinity. Although well folded and expressed, KRIT1(L717,721A) failed to target to EC junctions or complement the effects of KRIT1 depletion on zebrafish cardiovascular development or Rho kinase activation in EC. These data establish that this novel FERM–membrane protein interaction anchors CCM1/KRIT1 at EC junctions to support cardiovascular development.
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spelling pubmed-34615142013-04-01 Structural basis of the junctional anchorage of the cerebral cavernous malformations complex Gingras, Alexandre R. Liu, Jian J. Ginsberg, Mark H. J Cell Biol Research Articles The products of genes that cause cerebral cavernous malformations (CCM1/KRIT1, CCM2, and CCM3) physically interact. CCM1/KRIT1 links this complex to endothelial cell (EC) junctions and maintains junctional integrity in part by inhibiting RhoA. Heart of glass (HEG1), a transmembrane protein, associates with KRIT1. In this paper, we show that the KRIT1 band 4.1, ezrin, radixin, and moesin (FERM) domain bound the HEG1 C terminus (K(d) = 1.2 µM) and solved the structure of this assembly. The KRIT1 F1 and F3 subdomain interface formed a hydrophobic groove that binds HEG1(Tyr(1,380)-Phe(1,381)), thus defining a new mode of FERM domain–membrane protein interaction. This structure enabled design of KRIT1(L717,721A), which exhibited a >100-fold reduction in HEG1 affinity. Although well folded and expressed, KRIT1(L717,721A) failed to target to EC junctions or complement the effects of KRIT1 depletion on zebrafish cardiovascular development or Rho kinase activation in EC. These data establish that this novel FERM–membrane protein interaction anchors CCM1/KRIT1 at EC junctions to support cardiovascular development. The Rockefeller University Press 2012-10-01 /pmc/articles/PMC3461514/ /pubmed/23007647 http://dx.doi.org/10.1083/jcb.201205109 Text en © 2012 Gingras et al. 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/).
spellingShingle Research Articles
Gingras, Alexandre R.
Liu, Jian J.
Ginsberg, Mark H.
Structural basis of the junctional anchorage of the cerebral cavernous malformations complex
title Structural basis of the junctional anchorage of the cerebral cavernous malformations complex
title_full Structural basis of the junctional anchorage of the cerebral cavernous malformations complex
title_fullStr Structural basis of the junctional anchorage of the cerebral cavernous malformations complex
title_full_unstemmed Structural basis of the junctional anchorage of the cerebral cavernous malformations complex
title_short Structural basis of the junctional anchorage of the cerebral cavernous malformations complex
title_sort structural basis of the junctional anchorage of the cerebral cavernous malformations complex
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3461514/
https://www.ncbi.nlm.nih.gov/pubmed/23007647
http://dx.doi.org/10.1083/jcb.201205109
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