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PDBsum entry 3hh2
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Signaling protein/cytokine
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PDB id
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3hh2
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References listed in PDB file
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Key reference
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Title
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The structure of myostatin:follistatin 288: insights into receptor utilization and heparin binding.
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Authors
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J.N.Cash,
C.A.Rejon,
A.C.Mcpherron,
D.J.Bernard,
T.B.Thompson.
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Ref.
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Embo J, 2009,
28,
2662-2676.
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PubMed id
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Note: In the PDB file this reference is
annotated as "TO BE PUBLISHED". The citation details given above have
been manually determined.
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Abstract
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Myostatin is a member of the transforming growth factor-beta (TGF-beta) family
and a strong negative regulator of muscle growth. Here, we present the crystal
structure of myostatin in complex with the antagonist follistatin 288 (Fst288).
We find that the prehelix region of myostatin very closely resembles that of
TGF-beta class members and that this region alone can be swapped into activin A
to confer signalling through the non-canonical type I receptor Alk5.
Furthermore, the N-terminal domain of Fst288 undergoes conformational
rearrangements to bind myostatin and likely acts as a site of specificity for
the antagonist. In addition, 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.
Overall, 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.
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