The ability of a factor derived from platelets to stimulate the growth of fibroblasts, arterial smooth muscle cells, and glial cells in culture was discovered in the early 1970s. Over the next decade two forms of this platelet-derived growth factor, PDGF-A and PDGF-B, were characterized. In the early 2000s two more forms, PDGF-C and PDGF-D, were identified through genetic and protein biochemical approaches. Genes for the two receptors for PGDFs, PDGFRα, and PDGFRβ were characterized just prior to this time. Each of the PDGF forms and the two receptors are encoded by separate genes.
Figure 1 shows in schematic form the structural components of the PDGFs. In addition to a 20 amino acid signaling sequence, each of the four PDGFs contains a highly conserved core region which has eight strictly conserved cysteine residues. Six of these participate in a stability-promoting structure termed a cystine knot fold, in which one disulfide bridge passes through a loop formed by two other disulfide bridges. The remaining two cysteines form disulfide bridges between two protomers to form homodimers (AA, BB, CC, or DD) or, when both protomers are synthesized in the same cell, one heterodimer, AB. PDGF-C and PDGF-C do not appear to form heterodimers. PDGF dimerization occurs prior to secretion from the cell.
Fig1. Platelet-derived growth factors. The schematic structures of the four platelet-derived growth factors, PDGF-A, -B, -C, and -D, are shown. They contain a common conserved sequence (pink) of 95–112 amino acids which is the cystine-knot peptide that binds to the receptor. This portion of the protein contains three disulfide bonds that form a loop through which one of the three disulfide bridges passes, giving the peptide its stability and propensity to form dimers. Each PDGF also has a secretory sequence (green) and a pro-sequence (gray). The difference in the length of PDGFs A and B compared to C and D is largely accounted for by the difference in the length of this pro-sequence, with C and D containing the CUB (an acronym combining features of three peptide families) sequence. The double line between the pro-sequence and the conserved sequence indicates the cleavage between the two to release the active peptide. Finally, PDGFs A and B have a carboxy terminal tail (blue), sometimes referred to as a retention (R) sequence, consisting of positively charged amino acids which facilitate the binding of the released form to extracellular heparan sulfate.
Two features distinguish the A and B forms of PDGF from the C and D forms. The former have a carboxy terminal tail consisting of positively charged amino acids, promoting the interaction of the secreted factors with negatively charged pericellular molecules such as heparan sulfate, as described above for FGF. This retention sequence keeps the growth factors in the vicinity of the cells in which they will carry out their paracrine functions. PDGF-A can be alternatively spliced so that it lacks this carboxy terminal tail, in which case the secreted homodimer is fully soluble when it leaves the cell. PGDFs -C and -D lack this sequence, but have a longer pro sequence, containing a region (CUB; see legend to Figure 1) which may fulfill the same pericellular retention function.
The pro-sequences of dimers containing PDGF-A and/ or -B are removed at a specific cleavage site during secretion, whereas PDGFs -C and -D are secreted as latent forms with an intact pro-sequence which is then cleaved in the extracellular matrix. For PDGFs A, B, and D (and, perhaps C as well) the cleaved pro-sequences remain associated with the active peptide to maintain it in a latent form until the dimer binds to its cognate receptor.
