NMR Structure of Syndecan-4L reveals structural requirement for PKC signalling

Syndecans, transmembrane heparan sulfate proteoglycans, are coreceptors with integrin in cell adhesion process. It forms a ternary signaling complex with protein kinase C and phosphatidylinositol 4,5 bisphosphate (PIP2) for integrin signaling. NMR data indicates that cytoplasmic domain of syndecan-4 (4L) undergoes a conformational transition in the presence of PIP2, forming oligomeric conformation. The structure based on NMR data demonstrated that syndecan-4L itself forms a compact intertwined symmetric dimer with an unusual clamp shape for residues Leu$^{186}$ -Ala$^{195}$ . The molecular surface of the syndecan-4L dimer is highly positively charged. In addition, no inter-subunit NOEs in membrane proximal amino acid resides (Cl region) has been observed, demonstrating that the Cl region is mostly unstructured in syndecan-4L dimmer. However, the complex structure in the presence of PIP2 induced a high order multimeric conformation in solution. In addition, phosphorylation of cytoplasmic domain induces conformational change of syndecan-4, resulting inhibition of PKC signaling. The NMR structural data strongly suggest that PIP2 promotes oligomerization of syndecan-4 cytoplasmic domain for PKC activation and further induces structural reorganization of syndecan for mediating signaling network in cell adhesion procedure.