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From Proteopedia
Structure of activin A in complex with an ActRIIB-Alk4 fusion reveal insight into activin receptor interactions
Structural highlights
FunctionINHBA_HUMAN Inhibins and activins inhibit and activate, respectively, the secretion of follitropin by the pituitary gland. Inhibins/activins are involved in regulating a number of diverse functions such as hypothalamic and pituitary hormone secretion, gonadal hormone secretion, germ cell development and maturation, erythroid differentiation, insulin secretion, nerve cell survival, embryonic axial development or bone growth, depending on their subunit composition. Inhibins appear to oppose the functions of activins. Publication Abstract from PubMedThe 30+ unique ligands of the TGFbeta 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 TGFbeta 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. Structures of activin ligand traps using natural sets of type I and type II TGFbeta receptors.,Goebel EJ, Kattamuri C, Gipson GR, Krishnan L, Chavez M, Czepnik M, Maguire MC, Grenha R, Hakansson M, Logan DT, Grinberg AV, Sako D, Castonguay R, Kumar R, Thompson TB iScience. 2021 Dec 9;25(1):103590. doi: 10.1016/j.isci.2021.103590. eCollection , 2022 Jan 21. PMID:35005539[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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