title: Prodomains regulate the synthesis, extracellular localisation and activity of TGF-β superfamily ligands.
abstract: 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.
authors.affiliation: Prince Henry's Institute of Medical Research, Clayton, VIC 3168, Australia. craig.harrison@princehenrys.org
authors.forename: Craig A
authors.initials: CA
authors.lastname: Harrison
authors.forename: Sara L
authors.initials: SL
authors.lastname: Al-Musawi
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Walton
mesh_terms: D028341:Activins / Q000737:chemistry / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000737:chemistry / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000737:chemistry / Q000378:metabolism*; D000071837:Fibrillins; D055412:Growth Differentiation Factors / Q000737:chemistry / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007265:Inhibins / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008840:Microfilament Proteins / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D021382:Protein Sorting Signals; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D055411:TGF-beta Superfamily Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; D016326:Extracellular Matrix Proteins; D000071837:Fibrillins; D055412:Growth Differentiation Factors; D019812:Heparan Sulfate Proteoglycans; D008024:Ligands; D008840:Microfilament Proteins; D021382:Protein Sorting Signals; D055411:TGF-beta Superfamily Proteins; D028341:Activins; C071927:perlecan; D007265:Inhibins