Functionally diverse heteromeric traps for ligands of the transforming growth factor-β superfamily

Abstract Ligands of the transforming growth factor-β (TGF-β) superfamily are important targets for therapeutic intervention but present challenges because they signal combinatorially and exhibit overlapping activities in vivo. To obtain agents capable of sequestering multiple TGF-β superfamily ligan...

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Autores principales:	Ravindra Kumar, Asya V. Grinberg, Huiming Li, Tzu-Hsing Kuo, Dianne Sako, Lavanya Krishnan, Katia Liharska, Jia Li, Rosa Grenha, Michelle C. Maguire, Steven D. Briscoe, R. Scott Pearsall, Brantley R. Herrin, Rajasekhar N. V. S. Suragani, Roselyne Castonguay
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3cc08f92090942b6b1e99a5715b4ec9a
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spelling	oai:doaj.org-article:3cc08f92090942b6b1e99a5715b4ec9a2021-12-02T18:33:55ZFunctionally diverse heteromeric traps for ligands of the transforming growth factor-β superfamily10.1038/s41598-021-97203-92045-2322https://doaj.org/article/3cc08f92090942b6b1e99a5715b4ec9a2021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-97203-9https://doaj.org/toc/2045-2322Abstract Ligands of the transforming growth factor-β (TGF-β) superfamily are important targets for therapeutic intervention but present challenges because they signal combinatorially and exhibit overlapping activities in vivo. To obtain agents capable of sequestering multiple TGF-β superfamily ligands with novel selectivity, we generated soluble, heterodimeric ligand traps by pairing the extracellular domain (ECD) of the native activin receptor type IIB (ActRIIB) alternately with the ECDs of native type I receptors activin receptor-like kinase 4 (ALK4), ALK7, or ALK3. Systematic analysis of these heterodimeric constructs by surface plasmon resonance, and comparison with their homodimeric counterparts, revealed that each type I receptor partner confers a distinct ligand-binding profile to the heterodimeric construct. Additional characterization in cell-based reporter gene assays confirmed that the heterodimeric constructs possessed different profiles of signaling inhibition in vitro, which translated into altered patterns of pharmacological activity when constructs were administered systemically to wild-type mice. Our results detail a versatile platform for the modular recombination of naturally occurring receptor domains, giving rise to inhibitory ligand traps that could aid in defining the physiological roles of TGF-β ligand sets or be directed therapeutically to human diseases arising from dysregulated TGF-β superfamily signaling.Ravindra KumarAsya V. GrinbergHuiming LiTzu-Hsing KuoDianne SakoLavanya KrishnanKatia LiharskaJia LiRosa GrenhaMichelle C. MaguireSteven D. BriscoeR. Scott PearsallBrantley R. HerrinRajasekhar N. V. S. SuraganiRoselyne CastonguayNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ravindra Kumar Asya V. Grinberg Huiming Li Tzu-Hsing Kuo Dianne Sako Lavanya Krishnan Katia Liharska Jia Li Rosa Grenha Michelle C. Maguire Steven D. Briscoe R. Scott Pearsall Brantley R. Herrin Rajasekhar N. V. S. Suragani Roselyne Castonguay Functionally diverse heteromeric traps for ligands of the transforming growth factor-β superfamily
description	Abstract Ligands of the transforming growth factor-β (TGF-β) superfamily are important targets for therapeutic intervention but present challenges because they signal combinatorially and exhibit overlapping activities in vivo. To obtain agents capable of sequestering multiple TGF-β superfamily ligands with novel selectivity, we generated soluble, heterodimeric ligand traps by pairing the extracellular domain (ECD) of the native activin receptor type IIB (ActRIIB) alternately with the ECDs of native type I receptors activin receptor-like kinase 4 (ALK4), ALK7, or ALK3. Systematic analysis of these heterodimeric constructs by surface plasmon resonance, and comparison with their homodimeric counterparts, revealed that each type I receptor partner confers a distinct ligand-binding profile to the heterodimeric construct. Additional characterization in cell-based reporter gene assays confirmed that the heterodimeric constructs possessed different profiles of signaling inhibition in vitro, which translated into altered patterns of pharmacological activity when constructs were administered systemically to wild-type mice. Our results detail a versatile platform for the modular recombination of naturally occurring receptor domains, giving rise to inhibitory ligand traps that could aid in defining the physiological roles of TGF-β ligand sets or be directed therapeutically to human diseases arising from dysregulated TGF-β superfamily signaling.
format	article
author	Ravindra Kumar Asya V. Grinberg Huiming Li Tzu-Hsing Kuo Dianne Sako Lavanya Krishnan Katia Liharska Jia Li Rosa Grenha Michelle C. Maguire Steven D. Briscoe R. Scott Pearsall Brantley R. Herrin Rajasekhar N. V. S. Suragani Roselyne Castonguay
author_facet	Ravindra Kumar Asya V. Grinberg Huiming Li Tzu-Hsing Kuo Dianne Sako Lavanya Krishnan Katia Liharska Jia Li Rosa Grenha Michelle C. Maguire Steven D. Briscoe R. Scott Pearsall Brantley R. Herrin Rajasekhar N. V. S. Suragani Roselyne Castonguay
author_sort	Ravindra Kumar
title	Functionally diverse heteromeric traps for ligands of the transforming growth factor-β superfamily
title_short	Functionally diverse heteromeric traps for ligands of the transforming growth factor-β superfamily
title_full	Functionally diverse heteromeric traps for ligands of the transforming growth factor-β superfamily
title_fullStr	Functionally diverse heteromeric traps for ligands of the transforming growth factor-β superfamily
title_full_unstemmed	Functionally diverse heteromeric traps for ligands of the transforming growth factor-β superfamily
title_sort	functionally diverse heteromeric traps for ligands of the transforming growth factor-β superfamily
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/3cc08f92090942b6b1e99a5715b4ec9a
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Functionally diverse heteromeric traps for ligands of the transforming growth factor-β superfamily

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