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

Autor:	Aykul S; Regeneron Pharmaceuticals, Tarrytown, United States., Corpina RA; Regeneron Pharmaceuticals, Tarrytown, United States., Goebel EJ; University of Cincinnati, Cincinnati, United States., Cunanan CJ; Regeneron Pharmaceuticals, Tarrytown, United States., Dimitriou A; Regeneron Pharmaceuticals, Tarrytown, United States., Kim HJ; Regeneron Pharmaceuticals, Tarrytown, United States., Zhang Q; Regeneron Pharmaceuticals, Tarrytown, United States., Rafique A; Regeneron Pharmaceuticals, Tarrytown, United States., Leidich R; Regeneron Pharmaceuticals, Tarrytown, United States., Wang X; Regeneron Pharmaceuticals, Tarrytown, United States., McClain J; Regeneron Pharmaceuticals, Tarrytown, United States., Jimenez J; Regeneron Pharmaceuticals, Tarrytown, United States., Nannuru KC; Regeneron Pharmaceuticals, Tarrytown, United States., Rothman NJ; Regeneron Pharmaceuticals, Tarrytown, United States., Lees-Shepard JB; Regeneron Pharmaceuticals, Tarrytown, United States., Martinez-Hackert E; Michigan State University, East Lansing, United States., Murphy AJ; Regeneron Pharmaceuticals, Tarrytown, United States., Thompson TB; University of Cincinnati, Cincinnati, United States., Economides AN; Regeneron Pharmaceuticals, Tarrytown, United States., Idone V; Regeneron Pharmaceuticals, Tarrytown, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2020 Jun 09; Vol. 9. Date of Electronic Publication: 2020 Jun 09.
DOI:	10.7554/eLife.54582
Abstrakt:	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. Competing Interests: SA, RC, CC, AD, HK, QZ, AR, RL, XW, JM, JJ, KN, NR, JL, AM, AE, VI The author is an employee of Regeneron Pharmaceuticals, Inc. Regeneron is currently developing a monoclonal antibody that neutralizes Activin A (REGN2477) as a potential therapy in fibrodysplasia ossificans progressiva (see https://clinicaltrials.gov/ct2/show/NCT03188666). EG, EM, TT No competing interests declared (© 2020, Aykul et al.)
Databáze:	MEDLINE
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