Binding characteristics of PTP-BL PDZ domains.
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Publication year
2005Author(s)
Publisher
S.l. : s.n.
ISBN
9090198253
Number of pages
143 p.
Annotation
RU Radboud Universiteit Nijmegen, 15 december 2005
Promotor : Wieringa, B. Co-promotores : Hendriks, W.J.A.J., Vuister, G.W.
Publication type
Dissertation
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Organization
Cell Biology (UMC)
Subject
UMCN 3.1: Neuromuscular development and genetic disorders; UMCN 5.3: Cellular energy metabolismAbstract
In order to classify all PDZ domains of PTP-BL, we performed an unbiased screen for potential ligands using a random peptide library. Obtained results are consistent with reported data describing potential binding partners of PTP-BL (Chapter 2). Interestingly, we observed an altered PTP-BL PDZ2 peptide binding groove as a consequence of an allosteric interaction with PDZ1, thereby specifically hampering PDZ2 binding to class III targets. Thus, not only synergistic effects but also obstructing effects on PDZ binding of a specific subset of C-terminal targets may occur. As described in Chapter 3, PTP-BL PDZ3 displayed a preference for peptides that contain two cysteine residues. Additional data suggest that recognition of these C-terminal peptides is regulated by the formation of intramolecular disulfide bridges within the ligand. Chapter 4 describes studies addressing the mode of binding of PTP-BL PDZ 2 and 4 to the RIL protein in a physiological setting. Immunoprecipitations on lysates of transfected cells revealed that this interaction is a canonical interaction, dominated by the RIL C-terminal tail, with the RIL LIM domain playing an important role. In Chapter 5 we report that the association between Lats2 and PTP-BL is regulated through reversible phosphorylation of the P-1 tyrosine residue in the Lats2 C-terminus. Intriguingly, PTP-BL is able to dephosphorylate this residue, thereby regulating its own binding. Overexpression of Lats2 leads to a cell cycle block in the G1 phase. Inhibition of cell division does not require Lats2 C-terminal phosphorylation. However, a mild reduction in G1/S transition was noted upon removal of the Lats2 C-terminal PDZ binding site, suggesting a cooperative role for PTP-BL and Lats2 in the regulation of the cell cycle. In Chapter 6 the obtained results are discussed in relation to current literature. We propose three novel roles for PTP-BL, i.e. in catenin/cadherin-based signalling, redox sensing, and cell cycle regulation.
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