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

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Aykul S, Corpina RA, Goebel EJ, Cunanan CJ, Dimitriou A, Kim HJ, Zhang Q, Rafique A, Leidich R, Wang X, McClain J, Jimenez J, Nannuru KC, Rothman NJ, Lees-Shepard JB, Martinez-Hackert E, Murphy AJ, Thompson TB, Economides AN, Idone V

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. pii: 54582. doi: 10.7554/eLife.54582.

PubMed ID

32515349 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drugs

Garetosmab

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Garetosmab	Inhibin beta A chain	Protein	Humans	Yes	Binder	Details