A 16‐amino acid peptide from human α 2 ‐macroglobulin binds transforming growth factor‐β and platelet‐derived growth factor‐BB

α 2 ‐Macroglobulin (α 2 M) is a major carrier of transforming growth factor‐β (TGF‐β) in vitro and in vivo. By screening glutathione S‐transferase (GST) fusion proteins with overlapping sequences, we localized the TGF‐β‐binding site to aa 700–738 of the mature human α 2 M subunit. In separate experiments, we screened overlapping synthetic peptides corresponding to aa 696–777 of α 2 M and identified a single 16‐mer (718–733) that binds TGF‐β1. Platelet‐derived growth factor‐BB (PDGF‐BB) bound to the same peptide, even though TGF‐β and PDGF‐BB share almost no sequence identity. The sequence of the growth factor‐binding peptide, WDLVVVNSAGVAEVGV, included a high proportion of hydrophobic amino acids. The analogous peptide from murinoglobulin, a human α 2 M homologue that does not bind growth factors, contained only three nonconservative amino acid substitutions; however, the MUG peptide failed to bind TGF‐β1 and PDGF‐BB. These results demonstrate that a distinct and highly‐restricted site in α 2 M, positioned near the C‐terminal flank of the bait region, mediates growth factor binding. At least part of the growth factor‐binding site is encoded by exon 18 of the α 2 M gene, which is notable for a 5′ splice site polymorphism that has been implicated in Alzheimer's Disease.