The significance of valine 33 as a ligand-specific epitope of transforming growth factor α

Sarah M. Puddicombe, Stephen G. Chamberlin, Jennie MacGarvie, Audrey Richter, Douglas Robert Drummond, Jane Collins, Lynn Wood, Donna E. Davies

研究成果: ジャーナルへの寄稿記事

11 引用 (Scopus)

抄録

Although binding of epidermal growth factor (EGF) and transforming growth factor α (TGFα) to the EGF receptor (EGFR) is mutually competitive, their binding is not identical, and their biological activities are not always equivalent. To probe for ligand-specific interactions, we have synthesized analogues of TGFα with modifications to the residue lying between the fourth and fifth cysteines (the 'hinge'). Although this residue lies in a structurally conserved region of the protein, it is not conserved within the EGFR ligand family. Our results show that in TGFα there is a preference for a bulky hydrophobic hinge residue; this contrasts with EGF, for which a hydrogen bond donor functionality is preferred. Sequence analysis of the human EGFR ligands revealed that the nature of the hinge residue correlated with the sequence in the B-loop β-sheet. As this region is an important determinant in recognition of TGFα by the chicken EGFR, we assessed the mitogenicity of the TGFα hinge mutants, as well as the other EGFR ligands, using chicken embryo fibroblasts. The preference of the chicken EGFR for TGFα hinge mutants with hydrophobic side chains paralleled that of the human EGFR. Betacellulin and heparin-binding EGF-like growth factor also possess an hydrophobic hinge; both were at least as potent as TGFα for chicken embryo fibroblasts. EGF and amphiregulin, both with hydrogen bond donor functionalities at their hinge, displayed markedly decreased in potency by comparison with TGFα. We propose that EGFR ligands can be subclassified into TGFα-like and EGF-like and that this is of functional significance, identifying a potential mechanism whereby EGFR can discriminate between its ligands.

元の言語英語
ページ(範囲)15367-15372
ページ数6
ジャーナルJournal of Biological Chemistry
271
発行部数26
DOI
出版物ステータス出版済み - 7 16 1996

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Valine
Transforming Growth Factors
Epitopes
Hinges
Ligands
Epidermal Growth Factor Receptor
Epidermal Growth Factor
Chickens
Fibroblasts
Hydrogen
Hydrogen bonds
Embryonic Structures
Competitive Binding
Bioactivity
Cysteine
Sequence Analysis
Heparin
Intercellular Signaling Peptides and Proteins
EGF Family of Proteins

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

これを引用

Puddicombe, S. M., Chamberlin, S. G., MacGarvie, J., Richter, A., Drummond, D. R., Collins, J., ... Davies, D. E. (1996). The significance of valine 33 as a ligand-specific epitope of transforming growth factor α. Journal of Biological Chemistry, 271(26), 15367-15372. https://doi.org/10.1074/jbc.271.26.15367

The significance of valine 33 as a ligand-specific epitope of transforming growth factor α. / Puddicombe, Sarah M.; Chamberlin, Stephen G.; MacGarvie, Jennie; Richter, Audrey; Drummond, Douglas Robert; Collins, Jane; Wood, Lynn; Davies, Donna E.

:: Journal of Biological Chemistry, 巻 271, 番号 26, 16.07.1996, p. 15367-15372.

研究成果: ジャーナルへの寄稿記事

Puddicombe, SM, Chamberlin, SG, MacGarvie, J, Richter, A, Drummond, DR, Collins, J, Wood, L & Davies, DE 1996, 'The significance of valine 33 as a ligand-specific epitope of transforming growth factor α', Journal of Biological Chemistry, 巻. 271, 番号 26, pp. 15367-15372. https://doi.org/10.1074/jbc.271.26.15367
Puddicombe, Sarah M. ; Chamberlin, Stephen G. ; MacGarvie, Jennie ; Richter, Audrey ; Drummond, Douglas Robert ; Collins, Jane ; Wood, Lynn ; Davies, Donna E. / The significance of valine 33 as a ligand-specific epitope of transforming growth factor α. :: Journal of Biological Chemistry. 1996 ; 巻 271, 番号 26. pp. 15367-15372.
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