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Structural and Biochemical Insights into Myostatin Regulation

Cash, Jennifer N.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1313697112

Abstract Details

2011, PhD, University of Cincinnati, Medicine: Molecular Genetics, Biochemistry, and Microbiology.
Myostatin is a member of the transforming growth factor-β (TGF-β) family and a strong negative regulator of muscle growth. As such, myostatin is an attractive therapeutic target for the treatment of muscle-wasting diseases such as muscular dystrophy. Here, we present crystal structures of myostatin in complex with two antagonist molecules: follistatin (Fst) and Fst-like 3 (Fstl3). These represent the first and only published structures of myostatin. Furthermore, these are the only structures of Fst-type molecules in complex with a ligand other than activin A. Both Fst and Fstl3 are staunch inhibitors of myostatin, and Fstl3 is in fact the only Fst-type molecule that has been identified in the serum bound to myostatin. We find that the prehelix region of myostatin very closely resembles that of TGF-β class members and that this region alone can be swapped into activin A to confer signaling through the noncanonical type I receptor ALK5. Furthermore, the N-terminal domain (ND) of Fst288 undergoes conformational rearrangements to bind myostatin and likely acts as a site of specificity for the antagonist. Additionally, a unique continuous electropositive surface is created when myostatin binds Fst288, which significantly increases the affinity for heparin. This translates into stronger interactions with the cell surface and enhanced myostatin degradation in the presence of either Fst288 or Fst315. The ND of Fstl3 also interacts uniquely with myostatin as compared to activin A, as it utilizes different surfaces on the ligand. This results in conformational differences in the ND of Fstl3 that alter its position in the type I receptor-binding site of the ligand. The Fstl3 ND also exhibits less plasticity than that of Fst, and select point mutations in it are detrimental to Fstl3 function. Overall, we have shown that the NDs of Fst-type molecules exhibit distinctive modes of ligand binding, which may affect overall affinity of ligand:Fst-type protein complexes. Altogether, we have identified several characteristics unique to myostatin that will be paramount to the rational design of myostatin inhibitors that could be used in the treatment of muscle-wasting disorders.
Thomas Thompson, PhD (Committee Chair)
Sean Davidson, PhD (Committee Member)
Andrew Herr, PhD (Committee Member)
Rhett Kovall, PhD (Committee Member)
Jeff Molkentin, PhD (Committee Member)
134 p.
Biochemistry
myostatin; follistatin; activin A; TGF-beta; antagonist

Recommended Citations

Citations

  • Cash, J. N. (2011). Structural and Biochemical Insights into Myostatin Regulation [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1313697112

    APA Style (7th edition)

  • Cash, Jennifer. Structural and Biochemical Insights into Myostatin Regulation. 2011. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1313697112.

    MLA Style (8th edition)

  • Cash, Jennifer. "Structural and Biochemical Insights into Myostatin Regulation." Doctoral dissertation, University of Cincinnati, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1313697112

    Chicago Manual of Style (17th edition)

ucin1313697112
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© 2011, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.