Autoinhibition of the platelet-derived growth factor beta-receptor tyrosine kinase by its C-terminal tail
2004 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 279, no 19, 19732-19738 p.Article in journal (Refereed) Published
In this report, we investigated the role of the C-terminal tail of the platelet-derived growth factor (PDGF) beta-receptor in the control of the receptor kinase activity. Using a panel of PDGF beta-receptor mutants with progressive C-terminal truncations, we observed that deletion of the last 46 residues, which contain a proline- and glutamic acid-rich motif, increased the autoactivation velocity in vitro and the V(max) of the phosphotransfer reaction, in the absence of ligand, as compared with wild-type receptors. By contrast, the kinase activity of mutant and wild-type receptors that were pre-activated by treatment with PDGF was comparable. Using a conformation-sensitive antibody, we found that truncated receptors presented an active conformation even in the absence of PDGF. A soluble peptide containing the Pro/Glu-rich motif specifically inhibited the PDGF beta-receptor kinase activity. Whereas deletion of this motif was not enough to confer ligand-independent transforming ability to the receptor, it dramatically enhanced the effect of the weakly activating D850N mutation in a focus formation assay. These findings indicate that allosteric inhibition of the PDGF beta-receptor by its C-terminal tail is one of the mechanisms involved in keeping the receptor inactive in the absence of ligand.
Place, publisher, year, edition, pages
2004. Vol. 279, no 19, 19732-19738 p.
Amino Acid Motifs, Amino Acid Sequence, Animals, Blotting; Western, COS Cells, Dose-Response Relationship; Drug, Gene Deletion, Humans, Kinetics, Ligands, Models; Biological, Molecular Sequence Data, Mutagenesis; Site-Directed, Mutation, Peptides/chemistry, Protein Conformation, Protein Structure; Tertiary, Receptor; Platelet-Derived Growth Factor beta/chemistry/metabolism/*physiology, Research Support; Non-U.S. Gov't, Sequence Homology; Amino Acid, Time Factors, Transfection
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-72903DOI: 10.1074/jbc.M314070200PubMedID: 14996833OAI: oai:DiVA.org:uu-72903DiVA: diva2:100814