Activin A forms a non-signaling complex with ACVR1 and type II Activin/BMP receptors via its finger 2 tip loop
Open Access
- 9 June 2020
- journal article
- research article
- Published by eLife Sciences Publications, Ltd in eLife
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.Keywords
This publication has 49 references indexed in Scilit:
- Biochemical and Cellular Analysis Reveals Ligand Binding Specificities, a Molecular Basis for Ligand Recognition, and Membrane Association-dependent Activities of Cripto-1 and CrypticOnline Journal of Public Health Informatics, 2017
- Cytokine decoy and scavenger receptors as key regulators of immunity and inflammationCytokine, 2016
- Structure of Myostatin·Follistatin-like 3Online Journal of Public Health Informatics, 2012
- Activin A, a product of fetal Leydig cells, is a unique paracrine regulator of Sertoli cell proliferation and fetal testis cord expansionProceedings of the National Academy of Sciences of the United States of America, 2010
- The structure of myostatin:follistatin 288: insights into receptor utilization and heparin bindingThe EMBO Journal, 2009
- BMP-3 and BMP-6 Structures Illuminate the Nature of Binding Specificity with Receptors,Biochemistry, 2007
- Biology of RANK, RANKL, and osteoprotegerinArthritis Research & Therapy, 2007
- Growth differentiation factor 11 signals through the transforming growth factor‐β receptor ALK5 to regionalize the anterior–posterior axisEMBO Reports, 2006
- Structure of the ternary signaling complex of a TGF-β superfamily memberProceedings of the National Academy of Sciences of the United States of America, 2006
- Identification of human activin and TGFβ type I receptors that form heteromeric kinase complexes with type II receptorsCell, 1993