Structures of activin ligand traps using natural sets of type I and type II TGFβ receptors.
Biochemistry
Molecular biology
Structural biology
Journal
iScience
ISSN: 2589-0042
Titre abrégé: iScience
Pays: United States
ID NLM: 101724038
Informations de publication
Date de publication:
21 Jan 2022
21 Jan 2022
Historique:
received:
23
07
2021
revised:
18
11
2021
accepted:
06
12
2021
entrez:
10
1
2022
pubmed:
11
1
2022
medline:
11
1
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35005539
doi: 10.1016/j.isci.2021.103590
pii: S2589-0042(21)01560-1
pmc: PMC8718839
doi:
Types de publication
Journal Article
Langues
eng
Pagination
103590Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM134923
Pays : United States
Organisme : NIEHS NIH HHS
ID : T32 ES007250
Pays : United States
Informations de copyright
© 2021 The Authors.
Déclaration de conflit d'intérêts
T.B.T. is a consultant for Acceleron Pharma, a wholly owned subsidiary of Merck &Co., Inc.. R.C., R.G., L.K., M.C., M.C.M., D.S., and R.K. are current employees of Acceleron Pharma, a wholly owned subsidiary of Merck &Co., Inc.. M.H. and D.T.L. are current employees of SARomics Biostructures. The other authors declare no competing interests.
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