Structures of an ActRIIB:activin A complex reveal a novel binding mode for TGF-beta ligand:receptor interactions.
The TGF-beta superfamily of ligands and receptors stimulate cellular events in diverse processes ranging from cell fate specification in development to immune suppression. Activins define a major subgroup of TGF-beta ligands that regulate cellular differentiation, proliferation, activation and apoptosis. Activins signal through complexes formed with type I and type II serine/threonine kinase receptors. We have solved the crystal structure of activin A bound to the extracellular domain of a type II receptor, ActRIIB, revealing the details of this interaction. ActRIIB binds to the outer edges of the activin finger regions, with the two receptors juxtaposed in close proximity, in a mode that differs from TGF-beta3 binding to type II receptors. The dimeric activin A structure differs from other known TGF-beta ligand structures, adopting a compact folded-back conformation. The crystal structure of the complex is consistent with recruitment of two type I receptors into a close packed arrangement at the cell surface and suggests that diversity in the conformational arrangements of TGF-beta ligand dimers could influence cellular signaling processes.
Thompson
Thomas B
TB
Department of Biochemistry, Northwestern University, 2205 Tech Drive, Evanston, IL 60208, USA.
Woodruff
Teresa K
TK
Jardetzky
Theodore S
TS
D030301:Activin Receptors, Type II / Q000737:chemistry / Q000378:metabolism*; D028341:Activins / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D028322:Inhibin-beta Subunits / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D008024:Ligands; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C422405:activin A; D028341:Activins; D028322:Inhibin-beta Subunits; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B