Blocking the myostatin pathway

Blocking the myostatin pathway. Myostatin (M) activation requires stepwise proteolytic cleavages of the precursor protein. After the signal peptide (SP) is removed, a second cleavage event leaves two fragments: an N-terminal propeptide domain of ≈28 kD and C-terminal domain of 12.5 kD destined to become the active myostatin protein. Parallel fragments of the myostatin C-terminal are linked through a disulfide bond, referred to as the myostatin C-terminal dimer that remains noncovalently complexed to the N-terminal propeptide. This noncovalent complex circulates in the blood maintaining the myostatin C-terminal dimer in a latent, inactive state. A third cleavage at amino acid 76 affects the ability of the propeptide to bind the active C terminal domain. Myostatin can be found in the serum or locally in an inactive state when bound to follistatin (FS), follistatin-related gene (FLRG), and growth and differentiation factor-associated serum protein-1 (GASP-1). These peptides block the activation of the myostatin pathway. If the pathway is not inhibited, the active myostatin dimer binds to the activin receptor type IIB (ActRIIB), which then recruits and activates by transphosphorylation the type I receptor (ALK4 or ALK5). Smad2 and Smad3 are subsequently activated and form aggregates with Smad4 and then are translocated to the nucleus, activating target gene transcription.

Publication

INHIBITION OF MYOSTATIN WITH EMPHASIS ON FOLLISTATIN AS A THERAPY FOR MUSCLE DISEASE. () LOUISE R. RODINO-KLAPAC, et al. Muscle Nerve. ;39(3):283-296. Figure: F2. All organisms Drosophila melanogaster Homo sapiens

Disease mentions