Separate genes encode the two PDGF receptors, α and β. As shown in Figure 1A, the extracellular domain of the protomer consists of five Ig domains. D1 and D2 actually have a long linker between them, allowing the two domains to form a single structural module with a highly N-glycosylated hydrophilic N-terminal region to protect against nonspecific hydrophobic interactions at the D2 ligand binding site. Binding of the PDGF ligand dimer to two receptor protomers brings about receptor dimerization. The functional forms PDGFR are either a homodimer, αα or ββ, or heterodimer, αβ (Figure 1B). Structural studies indicate that while the linker between D2 and D3 is quite flexible, allowing the conformation of D3 to change significantly in response to ligand binding, the D3–D4 and D4–D5 linkers are rigid. This helps the change in conformation signal occurring in D3 upon ligand binding to be conveyed through the two remaining Ig domains and the plasma membrane to the intracellular signaling portion of the receptor. The intracellular portions of the PDGFRs have a juxtamembrane region, a split tyrosine kinase domain and a cytoplasmic tail, which is phosphorylated upon activation of the receptor.
Fig1. The PDGF receptor and ligand interactions. A. Structural features of the α and β forms of the PDGF receptor. The PDGF receptor consists of an extracellular domain containing five Ig loops, D1–D5 (green ovals), a transmembrane domain of about 25 amino acids, and an intracellular domain with a split tyrosine kinase. The binding of dimerized ligand (purple) promotes receptor protomer dimerization. Both homodimers and a heterodimer occur. Ligand binding takes place mostly on the hydrophobic surface of D2, which is closely associated with D1. The changes in D3 conformation brought about by ligand binding are passed through D4 and D5 by the more rigid D3–D4 and D4–D5 hinge regions (heavy bars) to the intracellular juxtamembrane region (JM) and the tyrosine kinase moieties. B. PDGF ligand-receptor interactions. The tendency of each of the four PDGF homodimers and one heterodimer (AB) to bind to each of the three forms of the PDGF receptor is shown.
Figure 1B shows the PDGFdimer/receptor dimer pairings that occur most often in vivo and in cells in tis sue culture. The PDGFRα homodimer binds three (AA, BB, CC) of the four homodimers with high affinity, whereas the PDGFβ homodimer binds the remaining homodimer (DD) as well as BB. The less restrictive amino acid composition of the ligand binding site of PDGFRα relative to PDGFRβ accounts for the greater promiscuity of the α homodimer. Similarly, PDGF-B is more flexible than the other PDGFs due to the less restrictive amino acids in its binding interface. Thus, BB homodimer can bind to all three forms of the PDGF receptor.
