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A 16-amino acid peptide from human α2-macroglobulin binds transforming growth factor-β and platelet-derived growth factor-BB

Published online by Cambridge University Press:  15 December 2000

DONNA J. WEBB
Affiliation:
Departments of Pathology, Biochemistry, and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia 22908
DAVID W. ROADCAP
Affiliation:
Departments of Pathology, Biochemistry, and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia 22908
ANITA DHAKEPHALKAR
Affiliation:
Departments of Pathology, Biochemistry, and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia 22908
STEVEN L. GONIAS
Affiliation:
Departments of Pathology, Biochemistry, and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia 22908
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Abstract

α2-Macroglobulin (α2M) 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 α2M subunit. In separate experiments, we screened overlapping synthetic peptides corresponding to aa 696–777 of α2M 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 α2M 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 α2M, 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 α2M gene, which is notable for a 5′ splice site polymorphism that has been implicated in Alzheimer's Disease.

Type
Research Article
Copyright
© 2000 The Protein Society

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