(a)TGF-β precursor undergoes proteolysis at its N-terminus (black arrow head) which results in the removal of its signal peptide. At the opposite end of the arm domain, LTBP binds the prodomain forming the “ring head” ( Figure 1). Two domains were defined in the structure: (i) an arm domain that contains an integrin-binding Arg-Gly-Asp (RGD) peptide motif and (ii) a “straitjacket” domain where the mature TGF-β is encased. Three-dimensional crystal structure of porcine latent TGF-β1 shows a conformation that resembles a ring-like shape. This complex subsequently covalently interacts with a second gene product, the latent TGF-β binding protein (LTBP), and is incorporated into a larger latent complex (LLC) that associates with the extracellular matrix (ECM). Regardless of this processing by furin, the mature and LAP domains remain associated by noncovalent bonds to form the small latent complex (SLC). The carboxy terminus corresponds to the functionally active cytokine and the large amino terminus is latency-associated protein (LAP), also referred to as the prodomain. Furin, a proprotein convertase, subsequently cleaves the protein into two fragments. The first signal peptide is cleaved in the rough endoplasmic reticulum.
The best characterized member of the TGF-β family, TGF-β1, is initially produced from a single gene as a large precursor known as pre- and pro-TGF-βs which undergo two proteolytic cleavage events. The TGF-β superfamily is now known to be composed of more than 30 chemokines such as TGF-β1-β3, activins, anti-Müllerian hormone (AMH), bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs) and NODAL that can signal via canonical and noncanonical receptors and intracellular effector proteins. Discovery of TGF-βs was the result of independent efforts by several laboratories during characterization of a secreted factor from fibroblasts transformed by the Moloney sarcoma virus (MSV).
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