ArticleFASEB bioAdvances2021
Inhibition of the HEG1-KRIT1 interaction increases KLF4 and KLF2 expression in endothelial cells.
Article in FASEB bioAdvances, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 18 citations in OpenAlex.
- Structure-based discovery of acridone alkaloids as disruptors of the HEG1-KRIT1 protein-protein interaction in cerebral cavernous malformation signaling.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2026Article
- Structure-based discovery of acridone alkaloids as disruptors of the HEG1-KRIT1 protein-protein interaction in cerebral cavernous malformation signaling.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2026Article
- Oxygenated 9H-carbazole-3-carbaldehyde scaffolds as cerebral cavernous malformation-relevant protein-protein interaction disruptors of the HEG1-KRIT1 interface.Journal of computer-aided molecular design · 2026Article
- Seq2Bind webserver for binding site prediction from sequences using fine-tuned protein language models.NAR genomics and bioinformatics · 2025Article
- HEG1 promotes gastric cancer progression by stabilizing AKT1 and is functionally regulated by the deubiquitinase USP48.European journal of medical research · 2025Article
- Advancing Covalent Ligand and Drug Discovery beyond Cysteine.Chemical reviews · 2025Review
- SilencingInternational journal of molecular sciences · 2025Article
- Krüppel-like factors in mitochondrial quality control.Frontiers in physiology · 2025Review
- Targeted Reversible Covalent Modification of a Noncatalytic Lysine of the Krev Interaction Trapped 1 Protein Enables Site-Directed Screening for Protein-Protein Interaction Inhibitors.ACS pharmacology & translational science · 2023Article
- Protein-protein interactions: developing small-molecule inhibitors/stabilizers through covalent strategies.Trends in pharmacological sciences · 2023Review
- Endothelial Differentiation ofInternational journal of molecular sciences · 2023Article
- Contribution of protein-protein interactions to the endothelial-barrier-stabilizing function of KRIT1.Journal of cell science · 2022Article
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Authors and funding
15 authors at 2 institutions in 1 country.
Funding
Abstract
The transmembrane protein heart of glass1 (HEG1) directly binds to and recruits Krev interaction trapped protein 1 (KRIT1) to endothelial junctions to form the HEG1-KRIT1 protein complex that establishes and maintains junctional integrity. Genetic inactivation or knockdown of endothelial HEG1 or KRIT1 leads to the upregulation of transcription factors Krüppel-like factors 4 and 2 (KLF4 and KLF2), which are implicated in endothelial vascular homeostasis; however, the effect of acute inhibition of the HEG1-KRIT1 interaction remains incompletely understood. Here, we report a high-throughput screening assay and molecular design of a small-molecule HEG1-KRIT1 inhibitor to uncover acute changes in signaling pathways downstream of the HEG1-KRIT1 protein complex disruption. The small-molecule HEG1-KRIT1 inhibitor 2 (HKi2) was demonstrated to be a bona fide inhibitor of the interaction between HEG1 and KRIT1 proteins, by competing orthosterically with HEG1 through covalent reversible interactions with the FERM (4.1, ezrin, radixin, and moesin) domain of KRIT1. The crystal structure of HKi2 bound to KRIT1 FERM revealed that it occupies the same binding pocket on KRIT1 as the HEG1 cytoplasmic tail. In human endothelial cells (ECs), acute inhibition of the HEG1-KRIT1 interaction by HKi2 increased KLF4 and KLF2 mRNA and protein levels, whereas a structurally similar inactive compound failed to do so. In zebrafish, HKi2 induced expression of klf2a in arterial and venous endothelium. Furthermore, genome-wide RNA transcriptome analysis of HKi2-treated ECs under static conditions revealed that, in addition to elevating KLF4 and KLF2 expression, inhibition of the HEG1-KRIT1 interaction mimics many of the transcriptional effects of laminar blood flow. Furthermore, HKi2-treated ECs also triggered Akt signaling in a phosphoinositide 3-kinase (PI3K)-dependent manner, as blocking PI3K activity blunted the Akt phosphorylation induced by HKi2. Finally, using an in vitro colocalization assay, we show that HKi6, an improved derivative of HKi2 with higher affinity for KRIT1, significantly impedes recruitment of KRIT1 to mitochondria-localized HEG1 in CHO cells, indicating a direct inhibition of the HEG1-KRIT1 interaction. Thus, our results demonstrate that early events of the acute inhibition of HEG1-KRIT1 interaction with HKi small-molecule inhibitors lead to: (i) elevated
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