Activin A forms a non-signaling complex with ACVR1 and type II Activin/BMP receptors via its finger 2 tip loop
- Regeneron Pharmaceuticals, United States
- University of Cincinnati, United States
- Michigan State University, United States
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.
Data availability
We are providing source files for the data shown in the main figures of the manuscript.
Article and author information
Author details
John B Lees-Shepard
Funding
The authors declare that there was no funding for this work.
Reviewing Editor
- Karen Lyons
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols.
Version history
- Received: December 19, 2019
- Accepted: June 8, 2020
- Accepted Manuscript published: June 9, 2020 (version 1)
- Version of Record published: June 30, 2020 (version 2)
- Version of Record updated: July 15, 2020 (version 3)
Copyright
© 2020, Aykul et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Activin A forms a non-signaling complex with ACVR1 and type II Activin/BMP receptors via its finger 2 tip loop
eLife 9:e54582.
https://doi.org/10.7554/eLife.54582
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