Abstract
BackgroundProtein tyrosine phosphatase PTPN13, also known as PTP-BL in mice, is a large multi-domain non-transmembrane scaffolding protein with a molecular mass of 270 kDa. It is involved in the regulation of several cellular processes such as cytokinesis and actin-cytoskeletal rearrangement. The modular structure of PTPN13 consists of an N-terminal KIND domain, a FERM domain, and five PDZ domains, followed by a C-terminal protein tyrosine phosphatase domain. PDZ domains are among the most abundant protein modules and they play a crucial role in signal transduction of protein networks.ResultsHere, we have analysed the binding characteristics of the isolated PDZ domains 2 and 3 from PTPN13 and compared them to the tandem domain PDZ2/3, which interacts with 12 C-terminal residues of the tumour suppressor protein of APC, using heteronuclear multidimensional NMR spectroscopy. Furthermore, we could show for the first time that PRK2 is a weak binding partner of PDZ2 and we demonstrate that the presence of PDZ3 alters the binding affinity of PDZ2 for APC, suggesting an allosteric effect and thereby modulating the binding characteristics of PDZ2. A HADDOCK-based molecular model of the PDZ2/3 tandem domain from PTPN13 supports these results.ConclusionsOur study of tandem PDZ2/3 in complex with APC suggests that the interaction of PDZ3 with PDZ2 induces an allosteric modulation within PDZ2 emanating from the back of the domain to the ligand binding site. Thus, the modified binding preference of PDZ2 for APC could be explained by an allosteric effect and provides further evidence for the pivotal function of PDZ2 in the PDZ123 domain triplet within PTPN13.
Highlights
Protein tyrosine phosphatase protein phosphatase non-receptor type 13 (PTPN13), known as Protein tyrosine phosphatase PTP-Basophil/Basophil-like (PTP)-BL in mice, is a large multi-domain nontransmembrane scaffolding protein with a molecular mass of 270 kDa
Peptide binding to PDZ domains of PTPN13 We have applied multidimensional heteronuclear nuclear magnetic resonance (NMR) spectroscopy in order to elucidate the binding affinities of the PDZ2 single domain and the tandem domain PDZ2/3 of PTPN13 for the chemically synthesized C-terminal dodecapeptides derived from adenomatous polyposis coli (APC) and protein kinase C-related kinase-2 (PRK2)
Taken together, our study suggests that the PDZ2 of PTPN13 plays a central role in the triplet cassette PDZ123 and that PDZ2 is regulated by the adjacent PDZ domains 1 and 3 (Fig. 7)
Summary
Protein tyrosine phosphatase PTPN13, known as PTP-BL in mice, is a large multi-domain nontransmembrane scaffolding protein with a molecular mass of 270 kDa. The modular structure of PTPN13 consists of an N-terminal KIND domain, a FERM domain, and five PDZ domains, followed by a C-terminal protein tyrosine phosphatase domain. PDZ domains are among the most abundant protein modules and they play a crucial role in signal transduction of protein networks. PTPN13 contains five PDZ domains and a Cterminal protein tyrosine phosphatase domain It has previously been reported for other PDZ-containing proteins, e.g. the glutamate receptor interacting protein (GRIP) and X11/Mint, that the binding characteristics of single domains differ from PDZ tandem and that allosteric effects can regulate the binding properties of PDZ tandem domains [10, 22, 23]
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