Autoinhibition of the platelet-derived growth factor beta-receptor tyrosine kinase by its C-terminal tail
(2004) Journal of Biological Chemistry — Vol. 279, n° 19, p. 19732-19738 (2004)
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- Abstract
- 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.
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Chiara, F., Bishayee, S., Heldin, C., & Demoulin, J. B. (2004). Autoinhibition of the platelet-derived growth factor beta-receptor tyrosine kinase by its C-terminal tail. Journal of Biological Chemistry, 279(19), 19732-19738. https://doi.org/10.1074/jbc.M314070200 (Original work published 2004)