Journal
FEBS JOURNAL
Volume 280, Issue 16, Pages 3822-3839Publisher
WILEY
DOI: 10.1111/febs.12377
Keywords
latent myostatin; myostatin; promyostatin; WFIKKN1; WFIKKN2
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Funding
- National Scientific Research Fund of Hungary (OTKA) [72125]
- National Office for Research and Technology of Hungary (NKTH) [TECH-09-A1-2009-0116]
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Myostatin, a negative regulator of skeletal muscle growth, is produced from myostatin precursor by multiple steps of proteolytic processing. After cleavage by a furin-type protease, the propeptide and growth factor domains remain associated, forming a noncovalent complex, the latent myostatin complex. Mature myostatin is liberated from latent myostatin by bone morphogenetic protein1/tolloid proteases. Here, we show that, in reporter assays, latent myostatin preparations have significant myostatin activity, as the noncovalent complex dissociates at an appreciable rate, and both mature and semilatent myostatin (a complex in which the dimeric growth factor domain interacts with only one molecule of myostatin propeptide) bind to myostatin receptor. WAP, Kazal, immunoglobulin, Kunitz and N domain-containing protein1 or growth and differentiation factor-associated serum protein2 (WFIKKN1), a large extracellular multidomain protein that binds both mature myostatin and myostatin propeptide [Kondas etal. (2008) J Biol Chem 283, 23677-23684]. Interestingly, the paralogous protein WAP, Kazal, immunoglobulin, Kunitz and N domain-containing protein2 or growth and differentiation factor-associated serum protein1 (WFIKKN2) was less efficient than WFIKKN1 as an antagonist of the interactions of myostatin receptor with semilatent myostatin. Our studies have shown that this difference is attributable to the fact that only WFIKKN1 has affinity for the propeptide domain, and this interaction increases its potency in suppressing the receptor-binding activity of semilatent myostatin. As the interaction of WFIKKN1 with various forms of myostatin permits tighter control of myostatin activity until myostatin is liberated from latent myostatin by bone morphogenetic protein1/tolloid proteases, WFIKKN1 may have greater potential as an antimyostatic agent than WFIKKN2.
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