Structural basis for ALK2/BMPR2 receptor complex signaling through kinase domain oligomerization

Agnew, Christopher; Ayaz, Pelin; Kashima, Risa; Loving, Hanna S.; Ghatpande, Prajakta; Kung, Jennifer E.; Underbakke, Eric S.; Shan, Yibing; Shaw, David E.; Hata, Akiko; Jura, Natalia

doi:10.1038/s41467-021-25248-5

Cited by 24 publications

(21 citation statements)

References 93 publications

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“…Tetrameric receptor complex structures were also found for the crystals of the EDs of ACVR2B/ALK1 complexed with BMP9, and the EDs of ACVR2A or 2B with ALK3 and BMP2 [ 35 , 49 , 50 ], and recently for the EDs of ACVR2B with ALK5 and GDF11 [ 9 ]. However, the cytoplasmic domains of the receptors also contribute to type I/type II heterocomplex formation, as shown by the reduced interactions between ALK5/TβRII and between BMPRII/ALK3 or ALK6 following truncation of parts of the cytoplasmic domains [ 42 , 46 ], and by the recent demonstration that the ALK2/BMPRII kinase domains form heterocomplexes via their C-terminal lobes [ 51 ].…”

Section: Introductionmentioning

confidence: 99%

Competition between type I activin and BMP receptors for binding to ACVR2A regulates signaling to distinct Smad pathways

et al. 2022

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Background Activins and bone morphogenetic proteins (BMPs) play critical, sometimes opposing roles, in multiple physiological and pathological processes and diseases. They signal to distinct Smad branches; activins signal mainly to Smad2/3, while BMPs activate mainly Smad1/5/8. This gives rise to the possibility that competition between the different type I receptors through which activin and BMP signal for common type II receptors can provide a mechanism for fine-tuning the cellular response to activin/BMP stimuli. Among the transforming growth factor-β superfamily type II receptors, ACVR2A/B are highly promiscuous, due to their ability to interact with different type I receptors (e.g., ALK4 vs. ALK2/3/6) and with their respective ligands [activin A (ActA) vs. BMP9/2]. However, studies on complex formation between these full-length receptors situated at the plasma membrane, and especially on the potential competition between the different activin and BMP type I receptors for a common activin type II receptor, were lacking. Results We employed a combination of IgG-mediated patching-immobilization of several type I receptors in the absence or presence of ligands with fluorescence recovery after photobleaching (FRAP) measurements on the lateral diffusion of an activin type II receptor, ACVR2A, to demonstrate the principle of competition between type I receptors for ACVR2. Our results show that ACVR2A can form stable heteromeric complexes with ALK4 (an activin type I receptor), as well as with several BMP type I receptors (ALK2/3/6). Of note, ALK4 and the BMP type I receptors competed for binding ACVR2A. To assess the implications of this competition for signaling output, we first validated that in our cell model system (U2OS cells), ACVR2/ALK4 transduce ActA signaling to Smad2/3, while BMP9 signaling to Smad1/5/8 employ ACVR2/ALK2 or ACVR2/ALK3. By combining ligand stimulation with overexpression of a competing type I receptor, we showed that differential complex formation of distinct type I receptors with a common type II receptor balances the signaling to the two Smad branches. Conclusions Different type I receptors that signal to distinct Smad pathways (Smad2/3 vs. Smad1/5/8) compete for binding to common activin type II receptors. This provides a novel mechanism to balance signaling between Smad2/3 and Smad1/5/8.

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Section: Introductionmentioning

confidence: 99%

Competition between type I activin and BMP receptors for binding to ACVR2A regulates signaling to distinct Smad pathways

et al. 2022

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“…The eutectic ligands isolated from the receptor and the active pocket of each target were identified using AutodockTools‐1.5.6, [17] Autodock Vina‐1.1.2 software was used to dock the active ingredients with the putative target molecules and determine its free binding energy. PyMOL software was used to visually analyze the interaction and binding patterns of active ingredients [18] …”

Section: Methodsmentioning

confidence: 99%

Network Pharmacology‐Based Approach for Investigating the Role of Xanthii Fructus in Treatment of Allergic Rhinitis

Yang

Zhang

et al. 2023

Chemistry & Biodiversity

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Xanthii Fructus (XF) has been used for treatment of allergic rhinitis (AR), but its pharmacological mechanism of action remains unclear. We aimed to explore the potential mechanism of XF in treatment of AR by using a network pharmacology approach combined with in vivo verification experiments in this study. We identified 945 AR-related pathogenic genes, 11 active components in XF and 178 targets of those active components by corresponding databases. Finally, 54 targets of active components from XF in treatment of AR were identified by the Protein-protein interaction (PPI) network, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, among which Tumor Necrosis Factor (TNF), Mitogen-activated Protein Kinase 3 (MAPK3), Prostaglandin G/H Synthase 2 (PTGS2), Epidermal Growth Factor Receptor (EGFR) showed strongest interactions. The molecular docking analysis showed that moupinamide could bind to EGFR at LEU704 and LEU703, and PTGS2 at TRP387; 24-Ethylcholest-4-en-3-one was identified to bind to MAPK3 at THR347. The validation of quantitative real-time reverse transcription PCR (RT-PCR) showed that XF decreased the levels of MAPK3, PTGS2, and EGFR expression in the nasal mucosa from AR mice gavaged with an XF water decoction. Meanwhile, the levels of interleukin (IL)-4, IL-5 and IL-13were also decreased after the treatment of XF by Enzyme-linked immunosorbent assay (ELISA). Our results provide the pharmacological mechanism and possible intervention targets of XF in treatment of AR.

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“…Autodock Vina-1.1.2 software ( Algethami et al, 2021 ) was used to dock the active ingredients with the putative target molecules and determine their free binding energy. PyMOL software was used to visually analyze the interaction and binding patterns of active ingredients ( Agnew et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

Network pharmacology analysis and experimental verification reveal the mechanism of the traditional Chinese medicine YU-Pingfeng San alleviating allergic rhinitis inflammatory responses

et al. 2022

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YU-Pingfeng San (YPFS) can regulate inflammatory response to alleviate the symptoms of nasal congestion and runny rose in allergic rhinitis (AR). However, the mechanism of action remains unclear. In this study, 30 active ingredients of three effective herbs included in YPFS and 140 AR/YPFS-related genes were identified by database analysis. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the targets were mainly enriched in immune inflammatory-related biological processes and pathways. Finally, three hub gene targeting epidermal growth factor receptor (EGFR), mitogen-activated protein kinase 1 (MAPK1), and protein kinase B1 (AKT1) related to YPFS and AR were identified by network pharmacology analysis. YPFS treatment decreased the expression of EGFR, MAPK1, and AKT1 in ovalbumin (OVA)-induced AR mice and impaired the production of inflammatory factors interleukin (IL)-4, IL-5, and IL-13, thus alleviating immunoglobulin E (IgE) production and the symptoms of scratching nose in AR. Through molecular docking analysis, we found that the active ingredients decursin, anomalin, and wogonin of YPFS could bind to EGFR, MAPK1, and AKT1 proteins. Moreover, decursin treatment impaired the expression of IL-4 and IL-5 in human PBMCs. These results suggested that YPFS could alleviate the AR inflammatory responses by targeting EGFR, MAPK1, and AKT1, showing the mechanism of action of YPFS in AR treatment.

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Structural basis for ALK2/BMPR2 receptor complex signaling through kinase domain oligomerization

Cited by 24 publications

References 93 publications

Competition between type I activin and BMP receptors for binding to ACVR2A regulates signaling to distinct Smad pathways

Competition between type I activin and BMP receptors for binding to ACVR2A regulates signaling to distinct Smad pathways

Network Pharmacology‐Based Approach for Investigating the Role of Xanthii Fructus in Treatment of Allergic Rhinitis

Network pharmacology analysis and experimental verification reveal the mechanism of the traditional Chinese medicine YU-Pingfeng San alleviating allergic rhinitis inflammatory responses

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