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The significance of Valine 33 as a ligand-specific epitope of transforming growth factor ?

The significance of Valine 33 as a ligand-specific epitope of transforming growth factor ?
The significance of Valine 33 as a ligand-specific epitope of transforming growth factor ?
Although binding of epidermal growth factor (EGF) and transforming growth factor ? (TGF?) 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 TGF? 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 TGF? 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 ?-sheet. As this region is an important determinant in recognition of TGF? by the chicken EGFR, we assessed the mitogenicity of the TGF? hinge mutants, as well as the other EGFR ligands, using chicken embryo fibroblasts. The preference of the chicken EGFR for TGF? 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 TGF? for chicken embryo fibroblasts. EGF and amphiregulin, both with hydrogen bond donor functionalities at their hinge, displayed markedly decreased in potency by comparison with TGF?. We propose that EGFR ligands can be subclassified into TGF?-like and EGF-like and that this is of functional significance, identifying a potential mechanism whereby EGFR can discriminate between its ligands.

0021-9258
15367-15372
Puddicombe, Sarah M.
124e2c4e-ab9a-46f3-855c-b54ed0b61cc4
Chamberlin, Stephen G.
ecb947dd-c59e-4c1d-b1f5-60aff91fbeb0
Macgarvie, Jennie
8b367b82-6afe-440f-8fa0-b6d02ceefa97
Richter, Audrey
5b4fb888-b3a7-4b81-a8a7-ffd2c046a196
Drummond, Douglas R.
934af439-7af8-45b3-afac-af5e744f379a
Collins, Jane
be0e66f1-3036-47fa-9d7e-914c48710ba4
Wood, Lynn
23143476-4a29-49df-8038-7f7b64313f5f
Davies, Donna E.
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Puddicombe, Sarah M.
124e2c4e-ab9a-46f3-855c-b54ed0b61cc4
Chamberlin, Stephen G.
ecb947dd-c59e-4c1d-b1f5-60aff91fbeb0
Macgarvie, Jennie
8b367b82-6afe-440f-8fa0-b6d02ceefa97
Richter, Audrey
5b4fb888-b3a7-4b81-a8a7-ffd2c046a196
Drummond, Douglas R.
934af439-7af8-45b3-afac-af5e744f379a
Collins, Jane
be0e66f1-3036-47fa-9d7e-914c48710ba4
Wood, Lynn
23143476-4a29-49df-8038-7f7b64313f5f
Davies, Donna E.
7de8fdc7-3640-4e3a-aa91-d0e03f990c38

Puddicombe, Sarah M., Chamberlin, Stephen G., Macgarvie, Jennie, Richter, Audrey, Drummond, Douglas R., Collins, Jane, Wood, Lynn and Davies, Donna E. (1996) The significance of Valine 33 as a ligand-specific epitope of transforming growth factor ? The Journal of Biological Chemistry, 271 (26), 15367-15372. (doi:10.1074/jbc.271.26.15367). (PMID:8663070)

Record type: Article

Abstract

Although binding of epidermal growth factor (EGF) and transforming growth factor ? (TGF?) 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 TGF? 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 TGF? 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 ?-sheet. As this region is an important determinant in recognition of TGF? by the chicken EGFR, we assessed the mitogenicity of the TGF? hinge mutants, as well as the other EGFR ligands, using chicken embryo fibroblasts. The preference of the chicken EGFR for TGF? 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 TGF? for chicken embryo fibroblasts. EGF and amphiregulin, both with hydrogen bond donor functionalities at their hinge, displayed markedly decreased in potency by comparison with TGF?. We propose that EGFR ligands can be subclassified into TGF?-like and EGF-like and that this is of functional significance, identifying a potential mechanism whereby EGFR can discriminate between its ligands.

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Published date: 28 June 1996

Identifiers

Local EPrints ID: 179831
URI: https://eprints.soton.ac.uk/id/eprint/179831
ISSN: 0021-9258
PURE UUID: 7d633eea-bbea-4a6a-b1d9-e71e3cc1ec34
ORCID for Donna E. Davies: ORCID iD orcid.org/0000-0002-5117-2991

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Date deposited: 08 Apr 2011 10:56
Last modified: 20 Jul 2019 01:28

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