Structural basis of the junctional anchorage of the cerebral cavernous malformations complex
Copyright policy )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, 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 (Kd = 1.2 µM) and solved the structure of this assembly. The KRIT1 F1 and F3 subdomain interface formed a hydrophobic groove that binds HEG1(Tyr1,380-Phe1,381), 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.
- University of California System United States
- University of California, San Diego United States
- University of California, San Diego United States
- University of California, San Francisco United States
- UNIVERSITY OF CALIFORNIA SAN DIEGO
Central Nervous System, Models, Molecular, Hemangioma, Cavernous, Central Nervous System, Protein Conformation, 1.1 Normal biological development and functioning, Cells, 610, Cardiovascular, Medical and Health Sciences, Cardiovascular System, Rare Diseases, Underpinning research, Models, Proto-Oncogene Proteins, Animals, Humans, KRIT1 Protein, Research Articles, Cells, Cultured, Zebrafish, rho-Associated Kinases, Cultured, Membrane Glycoproteins, Animal, Molecular, Endothelial Cells, Biological Sciences, Zebrafish Proteins, Brain Disorders, Disease Models, Animal, HEK293 Cells, Intercellular Junctions, Disease Models, Cavernous, Hemangioma, Microtubule-Associated Proteins, Developmental Biology, Signal Transduction
Central Nervous System, Models, Molecular, Hemangioma, Cavernous, Central Nervous System, Protein Conformation, 1.1 Normal biological development and functioning, Cells, 610, Cardiovascular, Medical and Health Sciences, Cardiovascular System, Rare Diseases, Underpinning research, Models, Proto-Oncogene Proteins, Animals, Humans, KRIT1 Protein, Research Articles, Cells, Cultured, Zebrafish, rho-Associated Kinases, Cultured, Membrane Glycoproteins, Animal, Molecular, Endothelial Cells, Biological Sciences, Zebrafish Proteins, Brain Disorders, Disease Models, Animal, HEK293 Cells, Intercellular Junctions, Disease Models, Cavernous, Hemangioma, Microtubule-Associated Proteins, Developmental Biology, Signal Transduction
selected citations These citations are derived from selected sources.This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).63 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 10%
Citations provided by BIP!Popularity provided by BIP!