ArticleThe Journal of biological chemistry2015
Structural basis for the disruption of the cerebral cavernous malformations 2 (CCM2) interaction with Krev interaction trapped 1 (KRIT1) by disease-associated mutations.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 43 citations in OpenAlex.
- Dual recruitment of two CCM2 molecules to KRIT1 suppresses KLF4 expression.Nature communications · 2026Article
- TLNRD1 is a CCM complex component and regulates endothelial barrier integrity.The Journal of cell biology · 2024Article
- KRIT1 in vascular biology and beyond.Bioscience reports · 2024Review
- Article
- Understanding ATP Binding to DosS Catalytic Domain with a Short ATP-Lid.Biochemistry · 2023Article
- Release of STK24/25 suppression on MEKK3 signaling in endothelial cells confers cerebral cavernous malformation.JCI insight · 2023Article
- Article
- Contribution of protein-protein interactions to the endothelial-barrier-stabilizing function of KRIT1.Journal of cell science · 2022Article
- Is Location Everything? Regulation of the Endothelial CCM Signaling Complex.Frontiers in cardiovascular medicine · 2022Review
- The multifacetedGenes & diseases · 2021Review
- Cerebral Cavernous Malformation 1 Determines YAP/TAZ Signaling-Dependent Metastatic Hallmarks of Prostate Cancer Cells.Cancers · 2021Article
- Protein kinase Cα regulates the nucleocytoplasmic shuttling of KRIT1.Journal of cell science · 2021Article
- Signalling through cerebral cavernous malformation protein networks.Open biology · 2020Review
- Serine phosphorylation of the small phosphoprotein ICAP1 inhibits its nuclear accumulation.The Journal of biological chemistry · 2020Article
- A NovelFrontiers in neuroscience · 2020Article
- Identification of a Novel CCM1 Frameshift Mutation in a Chinese Han Family With Multiple Cerebral Cavernous Malformations.Frontiers in neuroscience · 2020Article
- A Novel CCM2 Gene Mutation Associated With Cerebral Cavernous Malformation.Frontiers in neurology · 2020Article
- A conserved CCM complex promotes apoptosis non-autonomously by regulating zinc homeostasis.Nature communications · 2019Article
- Recent advances in cerebral cavernous malformation research.Vessel plus · 2018Article
- Introduction to cerebral cavernous malformation: a brief review.BMB reports · 2016Review
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
Familial cerebral cavernous malformations (CCMs) are predominantly neurovascular lesions and are associated with mutations within the KRIT1, CCM2, and PDCD10 genes. The protein products of KRIT1 and CCM2 (Krev interaction trapped 1 (KRIT1) and cerebral cavernous malformations 2 (CCM2), respectively) directly interact with each other. Disease-associated mutations in KRIT1 and CCM2 mostly result in loss of their protein products, although rare missense point mutations can also occur. From gene sequencing of patients known or suspected to have one or more CCMs, we discover a series of missense point mutations in KRIT1 and CCM2 that result in missense mutations in the CCM2 and KRIT1 proteins. To place these mutations in the context of the molecular level interactions of CCM2 and KRIT1, we map the interaction of KRIT1 and CCM2 and find that the CCM2 phosphotyrosine binding (PTB) domain displays a preference toward the third of the three KRIT1 NPX(Y/F) motifs. We determine the 2.75 Å co-crystal structure of the CCM2 PTB domain with a peptide corresponding to KRIT1(NPX(Y/F)3), revealing a Dab-like PTB fold for CCM2 and its interaction with KRIT1(NPX(Y/F)3). We find that several disease-associated missense mutations in CCM2 have the potential to interrupt the KRIT1-CCM2 interaction by destabilizing the CCM2 PTB domain and that a KRIT1 mutation also disrupts this interaction. We therefore provide new insights into the architecture of CCM2 and how the CCM complex is disrupted in CCM disease.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.