GDF-8 propeptide binds to GDF-8 and antagonizes biological activity by inhibiting GDF-8 receptor binding

RS Tries, T Chen, MV Da Vies, KN Tomkinson… - Growth …, 2001 - Taylor & Francis
RS Tries, T Chen, MV Da Vies, KN Tomkinson, AA Pearson, QA Shakey, NM Wolfman
Growth factors, 2001Taylor & Francis
GDF-8 is a new member of the TGF-β superfamily which appears to be a negative regulator
of skeletal muscle mass. Factors which regulate the biological activity of GDF-8 have not yet
been identified. However, the biological activities of TGF-β superfamily members, TGF-β1,-
β2 and-β3, can be inhibited by noncovalent association with TGF-β1,-β2 and β3 propeptides
cleaved from the amino-termini of the TGF-β precursor proteins. In contrast, the propeptides
of other TGF-β superfamily members do not appear to be inhibitory. In this investigation, we …
Abstract
GDF-8 is a new member of the TGF-β superfamily which appears to be a negative regulator of skeletal muscle mass. Factors which regulate the biological activity of GDF-8 have not yet been identified. However, the biological activities of TGF-β superfamily members, TGF-β1,-β2 and-β3, can be inhibited by noncovalent association with TGF-β1,-β2 and β3 propeptides cleaved from the amino-termini of the TGF-β precursor proteins. In contrast, the propeptides of other TGF-β superfamily members do not appear to be inhibitory. In this investigation, we demonstrate that purified recombinant GDF-8 propeptide associates with purified recombinant GDF-8 to form a noncovalent complex, as evidenced by size exclusion chromatography and chemical crosslinking analysis. Furthermore, we show that GDF-8 propeptide inhibits the biological activity of GDF-8 assayed on A204 rhabdomyosarcoma cells transfected with a (CAGA)12 reporter construct. Finally, we demonstrate that GDF-8 propeptide inhibits specific GDF-8 binding to L6 myoblast cells. Collectively, these data identify the GDF-8 propeptide as an inhibitor of GDF-8 biological activity.
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