Structures of activin ligand traps using natural sets of type I and type II TGFβ receptors
Summary: The 30+ unique ligands of the TGFβ family signal by forming complexes using different combinations of type I and type II receptors. Therapeutically, the extracellular domain of a single receptor fused to an Fc molecule can effectively neutralize subsets of ligands. Increased ligand specific...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-01-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004221015601 |
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| author | Erich J. Goebel Chandramohan Kattamuri Gregory R. Gipson Lavanya Krishnan Moises Chavez Magdalena Czepnik Michelle C. Maguire Rosa Grenha Maria Håkansson Derek T. Logan Asya V. Grinberg Dianne Sako Roselyne Castonguay Ravindra Kumar Thomas B. Thompson |
| author_facet | Erich J. Goebel Chandramohan Kattamuri Gregory R. Gipson Lavanya Krishnan Moises Chavez Magdalena Czepnik Michelle C. Maguire Rosa Grenha Maria Håkansson Derek T. Logan Asya V. Grinberg Dianne Sako Roselyne Castonguay Ravindra Kumar Thomas B. Thompson |
| author_sort | Erich J. Goebel |
| collection | DOAJ |
| description | Summary: The 30+ unique ligands of the TGFβ family signal by forming complexes using different combinations of type I and type II receptors. Therapeutically, the extracellular domain of a single receptor fused to an Fc molecule can effectively neutralize subsets of ligands. Increased ligand specificity can be accomplished by using the extracellular domains of both the type I and type II receptor to mimic the naturally occurring signaling complex. Here, we report the structure of one “type II-type I-Fc” fusion, ActRIIB-Alk4-Fc, in complex with two TGFβ family ligands, ActA, and GDF11, providing a snapshot of this therapeutic platform. The study reveals that extensive contacts are formed by both receptors, replicating the ternary signaling complex, despite the inherent low affinity of Alk4. Our study shows that low-affinity type I interactions support altered ligand specificity and can be visualized at the molecular level using this platform. |
| first_indexed | 2024-12-20T16:00:39Z |
| format | Article |
| id | doaj.art-0b41a10071f446298a7ec2b0eff0ed7a |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-20T16:00:39Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-0b41a10071f446298a7ec2b0eff0ed7a2022-12-21T19:34:17ZengElsevieriScience2589-00422022-01-01251103590Structures of activin ligand traps using natural sets of type I and type II TGFβ receptorsErich J. Goebel0Chandramohan Kattamuri1Gregory R. Gipson2Lavanya Krishnan3Moises Chavez4Magdalena Czepnik5Michelle C. Maguire6Rosa Grenha7Maria Håkansson8Derek T. Logan9Asya V. Grinberg10Dianne Sako11Roselyne Castonguay12Ravindra Kumar13Thomas B. Thompson14Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, 231 Albert Sabin Way ML 0524, Cincinnati, OH 45267, USADepartment of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, 231 Albert Sabin Way ML 0524, Cincinnati, OH 45267, USADepartment of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, 231 Albert Sabin Way ML 0524, Cincinnati, OH 45267, USAAcceleron Pharma, Inc., Cambridge, MA 02139, USAAcceleron Pharma, Inc., Cambridge, MA 02139, USADepartment of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, 231 Albert Sabin Way ML 0524, Cincinnati, OH 45267, USAAcceleron Pharma, Inc., Cambridge, MA 02139, USAAcceleron Pharma, Inc., Cambridge, MA 02139, USASARomics Biostructures AB, Medicon Village, Scheeletorget 1, 223 63, Lund, SwedenSARomics Biostructures AB, Medicon Village, Scheeletorget 1, 223 63, Lund, SwedenDragonfly Therapeutics, Waltham, MA 02451, USAAcceleron Pharma, Inc., Cambridge, MA 02139, USAAcceleron Pharma, Inc., Cambridge, MA 02139, USAAcceleron Pharma, Inc., Cambridge, MA 02139, USADepartment of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, 231 Albert Sabin Way ML 0524, Cincinnati, OH 45267, USA; Corresponding authorSummary: The 30+ unique ligands of the TGFβ family signal by forming complexes using different combinations of type I and type II receptors. Therapeutically, the extracellular domain of a single receptor fused to an Fc molecule can effectively neutralize subsets of ligands. Increased ligand specificity can be accomplished by using the extracellular domains of both the type I and type II receptor to mimic the naturally occurring signaling complex. Here, we report the structure of one “type II-type I-Fc” fusion, ActRIIB-Alk4-Fc, in complex with two TGFβ family ligands, ActA, and GDF11, providing a snapshot of this therapeutic platform. The study reveals that extensive contacts are formed by both receptors, replicating the ternary signaling complex, despite the inherent low affinity of Alk4. Our study shows that low-affinity type I interactions support altered ligand specificity and can be visualized at the molecular level using this platform.http://www.sciencedirect.com/science/article/pii/S2589004221015601BiochemistryMolecular biologyStructural biology |
| spellingShingle | Erich J. Goebel Chandramohan Kattamuri Gregory R. Gipson Lavanya Krishnan Moises Chavez Magdalena Czepnik Michelle C. Maguire Rosa Grenha Maria Håkansson Derek T. Logan Asya V. Grinberg Dianne Sako Roselyne Castonguay Ravindra Kumar Thomas B. Thompson Structures of activin ligand traps using natural sets of type I and type II TGFβ receptors iScience Biochemistry Molecular biology Structural biology |
| title | Structures of activin ligand traps using natural sets of type I and type II TGFβ receptors |
| title_full | Structures of activin ligand traps using natural sets of type I and type II TGFβ receptors |
| title_fullStr | Structures of activin ligand traps using natural sets of type I and type II TGFβ receptors |
| title_full_unstemmed | Structures of activin ligand traps using natural sets of type I and type II TGFβ receptors |
| title_short | Structures of activin ligand traps using natural sets of type I and type II TGFβ receptors |
| title_sort | structures of activin ligand traps using natural sets of type i and type ii tgfβ receptors |
| topic | Biochemistry Molecular biology Structural biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004221015601 |
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