Activin A forms a non-signaling complex with ACVR1 and type II Activin/BMP receptors via its finger 2 tip loop.

ELife
Senem AykulVincent Idone

Abstract

Activin A functions in BMP signaling in two ways: it either engages ACVR1B to activate Smad2/3 signaling or binds ACVR1 to form a non-signaling complex (NSC). Although the former property has been studied extensively, the roles of the NSC remain unexplored. The genetic disorder fibrodysplasia ossificans progressiva (FOP) provides a unique window into ACVR1/Activin A signaling because in that disease Activin can either signal through FOP-mutant ACVR1 or form NSCs with wild-type ACVR1. To explore the role of the NSC, we generated 'agonist-only' Activin A muteins that activate ACVR1B but cannot form the NSC with ACVR1. Using one of these muteins, we demonstrate that failure to form the NSC in FOP results in more severe disease pathology. These results provide the first evidence for a biological role for the NSC in vivo and pave the way for further exploration of the NSC's physiological role in corresponding knock-in mice.

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Citations

Oct 23, 2020·Cytokine & Growth Factor Reviews·Erik Martinez-HackertToril Holien
Mar 7, 2021·Biomedicines·Francesc VenturaGonzalo Sanchez-Duffhues
May 19, 2021·The EMBO Journal·Anassuya RamachandranCaroline S Hill
Sep 17, 2021·Scientific Reports·Ravindra KumarRoselyne Castonguay

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Methods Mentioned

BETA
Profiler
ion exchange chromatography
Surface Plasmon Resonance
chip
surface
biosensor
size exclusion chromatography
reverse phase chromatography
chips
Assay

Software Mentioned

Image J
PyMol
MacVector
YASARA
ClustalW
Scrubber
Clustal
STRAP
Analyze
PyMol Molecular Graphics System

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