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

Elife. 2020 Jun 9;9:e54582. doi: 10.7554/eLife.54582.

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.

Trial registration: ClinicalTrials.gov NCT03188666.

Keywords: ACVR1; ACVR1B; activin A; biochemistry; bone morphogenetic proteins; cell biology; chemical biology; fibrodysplasia ossificans progressiva; mouse; signal transduction.

MeSH terms

  • Activin Receptors, Type I / genetics
  • Activin Receptors, Type I / metabolism*
  • Activins / genetics
  • Activins / metabolism*
  • Animals
  • Bone Morphogenetic Protein Receptors, Type II / genetics
  • Bone Morphogenetic Protein Receptors, Type II / metabolism
  • Bone Morphogenetic Proteins / genetics
  • Bone Morphogenetic Proteins / metabolism*
  • Gene Knock-In Techniques
  • Mice
  • Mice, Transgenic
  • Mutation
  • Myositis Ossificans / genetics*
  • Myositis Ossificans / pathology
  • Signal Transduction / genetics*

Substances

  • Bone Morphogenetic Proteins
  • activin A
  • Activins
  • Activin Receptors, Type I
  • Acvr1 protein, mouse
  • Acvr1b protein, mouse
  • Bone Morphogenetic Protein Receptors, Type II

Associated data

  • ClinicalTrials.gov/NCT03188666