Group:MUZIC:Myostatin

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Growth/differentiation factor 8 or Myostatin

The structure of myostatin:follistatin 288 (PDB 3hh2)

Drag the structure with the mouse to rotate


Introduction

Myostatin which is also known as growth/differentiation factor-8 (GDF-8) was originally identified in a screen for novel mammalian members of the transforming growth factor-ß (TGF-ß) superfamily of growth and differentiation factors.The phenotype of myostatin knock-out mice suggested that myostatin functions as a negative regulator of muscle growth, and it was on this basis that myostatin was given its name [1]. For these reasons, inhibitors targeting myostatin have been regarded as potential drugs in the treatment of muscle-wasting disorders such as muscular dystrophy [2].

Sequence annotation

Myostatin is a 375 amino-acid protein consisting of three functional fragments (Uniprot:O14793): signal peptide, N-terminal and C-terminal fragments. Amino acid sequences among vertebrate species are highly conserved, which also suggests the conserved function of myostatin among vertebrates [3].

Image:myostatin.jpg

Structure

The complex of two follistatin 288 molecules bound to one myostatin dimer was resolved to 2.15 Å using X-ray crystallography and deposited in PDB. Myostatin shows a typical hand-shaped structure of TGF-beta family. When myostatin binds to Fst288, which increase the affinity to heparin due to the continuous basic surface of the complex [4]. (Green:myostatin C-terminal dimer, yellow: follinstatin 288)

Image:Myo2.png

Function and Interactions

Myostatin is initially formed as a precursor protein which undergoes two proteolytic processing events in order to generate the biologically active molecule. First the N-terminal signal sequence is removed, a second cleavage generates the C-terminal fragment, which possesses receptor-binding activity and modulates a signal transduction cascade in the target cell [5]. The N-terminal fragment after proteolytic processing has been referred to as the propeptide (shown blue). One mechanism for activating myostatin latency appears to be proteolytic cleavage of the propeptide [6]. In addition to the regulation of intracellular myostation processing,follistatin has been known to be capable of binding and inhibiting the activity of the myostatin C-terminal dimer (shown yellow). [7].

The interaction of myostatin with titin-cap(T-cap),a Z-disk protein which binds to N-terminal domain of titin,was identified by a yeast two-hybrid system. [8] It is presumed that myostatin has a putative role in the muscle Z-disk regulation.


Image:Myo1.gif (Processing of myostatin protein. Lee,2004)

Pathology

Mice lacking C-terminal domain of myostatin shows dramatic increases in skeletal muscle mass, which are observed for the entire life of mice. In addition, myostatin mutant mice fail to accumulate fat as a function of age and suppress the development of insulin resistance [9]. Thus, the targeting myostatin pathway might be an effective way to promote muscle growth for the patients with muscle degenerative diseases, such as muscular dystrophy and to prevent obesity [10].

References

  1. McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature. 1997 May 1;387(6628):83-90. PMID:9139826 doi:10.1038/387083a0
  2. Bradley L, Yaworsky PJ, Walsh FS. Myostatin as a therapeutic target for musculoskeletal disease. Cell Mol Life Sci. 2008 Jul;65(14):2119-24. PMID:18425412 doi:10.1007/s00018-008-8077-3
  3. McPherron AC, Lee SJ. Double muscling in cattle due to mutations in the myostatin gene. Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12457-61. PMID:9356471
  4. Cash JN, Rejon CA, McPherron AC, Bernard DJ, Thompson TB. The structure of myostatin:follistatin 288: insights into receptor utilization and heparin binding. EMBO J. 2009 Sep 2;28(17):2662-76. Epub 2009 Jul 30. PMID:19644449 doi:10.1038/emboj.2009.205
  5. Lee SJ. Regulation of muscle mass by myostatin. Annu Rev Cell Dev Biol. 2004;20:61-86. PMID:15473835 doi:10.1146/annurev.cellbio.20.012103.135836
  6. Wolfman NM, McPherron AC, Pappano WN, Davies MV, Song K, Tomkinson KN, Wright JF, Zhao L, Sebald SM, Greenspan DS, Lee SJ. Activation of latent myostatin by the BMP-1/tolloid family of metalloproteinases. Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15842-6. Epub 2003 Dec 11. PMID:14671324 doi:10.1073/pnas.2534946100
  7. Nakamura T, Takio K, Eto Y, Shibai H, Titani K, Sugino H. Activin-binding protein from rat ovary is follistatin. Science. 1990 Feb 16;247(4944):836-8. PMID:2106159
  8. Nicholas G, Thomas M, Langley B, Somers W, Patel K, Kemp CF, Sharma M, Kambadur R. Titin-cap associates with, and regulates secretion of, Myostatin. J Cell Physiol. 2002 Oct;193(1):120-31. PMID:12209887 doi:10.1002/jcp.10158
  9. McPherron AC, Lee SJ. Suppression of body fat accumulation in myostatin-deficient mice. J Clin Invest. 2002 Mar;109(5):595-601. PMID:11877467 doi:10.1172/JCI13562
  10. Lee SJ. Regulation of muscle mass by myostatin. Annu Rev Cell Dev Biol. 2004;20:61-86. PMID:15473835 doi:10.1146/annurev.cellbio.20.012103.135836

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