Structures of activin ligand traps using natural sets of type I and type II TGFβ receptors
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
Affiliations
Erich J. Goebel
Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, 231 Albert Sabin Way ML 0524, Cincinnati, OH 45267, USA
Chandramohan Kattamuri
Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, 231 Albert Sabin Way ML 0524, Cincinnati, OH 45267, USA
Gregory R. Gipson
Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, 231 Albert Sabin Way ML 0524, Cincinnati, OH 45267, USA
Lavanya Krishnan
Acceleron Pharma, Inc., Cambridge, MA 02139, USA
Moises Chavez
Acceleron Pharma, Inc., Cambridge, MA 02139, USA
Magdalena Czepnik
Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, 231 Albert Sabin Way ML 0524, Cincinnati, OH 45267, USA
Michelle C. Maguire
Acceleron Pharma, Inc., Cambridge, MA 02139, USA
Rosa Grenha
Acceleron Pharma, Inc., Cambridge, MA 02139, USA
Maria Håkansson
SARomics Biostructures AB, Medicon Village, Scheeletorget 1, 223 63, Lund, Sweden
Derek T. Logan
SARomics Biostructures AB, Medicon Village, Scheeletorget 1, 223 63, Lund, Sweden
Asya V. Grinberg
Dragonfly Therapeutics, Waltham, MA 02451, USA
Dianne Sako
Acceleron Pharma, Inc., Cambridge, MA 02139, USA
Roselyne Castonguay
Acceleron Pharma, Inc., Cambridge, MA 02139, USA
Ravindra Kumar
Acceleron Pharma, Inc., Cambridge, MA 02139, USA
Thomas B. Thompson
Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, 231 Albert Sabin Way ML 0524, Cincinnati, OH 45267, USA; Corresponding author
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.
