Prodomains regulate the synthesis, extracellular localisation and activity of TGF-β superfamily ligands

Growth Factors. 2011 Oct;29(5):174-86. doi: 10.3109/08977194.2011.608666. Epub 2011 Aug 24.


All transforming growth factor-β (TGF-β) ligands are synthesised as precursor molecules consisting of a signal peptide, an N-terminal prodomain and a C-terminal mature domain. During synthesis, prodomains interact non-covalently with mature domains, maintaining the molecules in a conformation competent for dimerisation. Dimeric precursors are cleaved by proprotein convertases, and TGF-β ligands are secreted from the cell non-covalently associated with their prodomains. Extracellularly, prodomains localise TGF-β ligands within the vicinity of their target cells via interactions with extracellular matrix proteins, including fibrillin and perlecan. For some family members (TGF-β1, TGF-β2, TGF-β3, myostatin, GDF-11 and BMP-10), prodomains bind with high enough affinity to suppress biological activity. The subsequent mechanism of activation of these latent TGF-β ligands varies according to cell type and context, but all activating mechanisms directly target prodomains. Thus, prodomains control many aspects of TGF-β superfamily biology, and alterations in prodomain function are often associated with disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activins / chemistry
  • Activins / metabolism
  • Bone Morphogenetic Proteins / chemistry
  • Bone Morphogenetic Proteins / metabolism
  • Extracellular Matrix Proteins / chemistry
  • Extracellular Matrix Proteins / metabolism*
  • Fibrillins
  • Growth Differentiation Factors / chemistry
  • Growth Differentiation Factors / metabolism
  • Heparan Sulfate Proteoglycans / chemistry
  • Heparan Sulfate Proteoglycans / metabolism
  • Humans
  • Inhibins / chemistry
  • Inhibins / metabolism
  • Ligands
  • Microfilament Proteins / chemistry
  • Microfilament Proteins / metabolism
  • Protein Binding
  • Protein Sorting Signals
  • Protein Structure, Tertiary
  • Signal Transduction
  • TGF-beta Superfamily Proteins / chemistry*
  • TGF-beta Superfamily Proteins / metabolism*


  • Bone Morphogenetic Proteins
  • Extracellular Matrix Proteins
  • Fibrillins
  • Growth Differentiation Factors
  • Heparan Sulfate Proteoglycans
  • Ligands
  • Microfilament Proteins
  • Protein Sorting Signals
  • TGF-beta Superfamily Proteins
  • Activins
  • perlecan
  • Inhibins