Binding affinity of transforming growth factor-β for its type II receptor is determined by the C-terminal region of the molecule

Su Wen Qian, James K. Burmester, Monica L.S. Tsang, James A. Weatherbee, Andrew P. Hinck, Dennis J. Ohlsen, Michael B. Sporn, Anita B. Roberts

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Transforming growth factor-β (TGF-β) isoforms have differential binding affinities for the TGF-β type II receptor (TβRII). In most cells, TGF-β1 and TGF-β3 bind to TβRII with much higher affinity than TGF-β2. Here, we report an analysis of the effect of TGF-β structure on its binding to TβRII by using TGF-β mutants with domain deletions, amino acid replacements, and isoform chimeras. Examination of the binding of TGF-β mutants to the recombinant extracellular domain of TβRII by a solid-phase TGF-β/TβRII assay demonstrated that only those TGF-β mutants containing the C terminus of TGF-β1 (TGF-β1-(Δ69-73), TGF-β1-(Trp71), and TGF- β2/β1-(83112)) bind with high affinity to TβRII, similar to native TGF- β1. Moreover, replacement of only 6 amino acids in the C terminus of TGF- β1 with the corresponding sequence of TGF-β2 (TGF-β1/β2-(91-96)) completely eliminated the high affinity binding of TGF-β1. Proliferation of fetal bovine heart endothelial (FBHE) cells was inhibited to a similar degree by all of the TGF-β mutants. However, recombinant soluble TβRII blocked the inhibition of FBHE cell proliferation induced by TGF-β mutants retaining the C terminus of TGF-β1, consistent with the high binding affinity between these TGF-β molecules and TβRII. It was further confirmed that the TGF-β2 mutant with its C terminus replaced by that of TGF-β1 (TGF-β2/β1-(83- 112)) competed as effectively as TGF-β1 with 125I-TGF-β1 for binding to membrane TβRI and TβRH on FBHE cells. These observations clearly indicate that the domain in TGF-β1 responsible for its high affinity binding to TβRII, both the soluble and membrane-bound forms, is located at C terminus of the molecule.

Original languageEnglish (US)
Pages (from-to)30656-30662
Number of pages7
JournalJournal of Biological Chemistry
Volume271
Issue number48
DOIs
StatePublished - 1996

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Binding affinity of transforming growth factor-β for its type II receptor is determined by the C-terminal region of the molecule'. Together they form a unique fingerprint.

Cite this