Periaxin and AHNAK Nucleoprotein 2 Form Intertwined Homodimers through Domain Swapping

Background: Periaxin and AHNAK nucleoprotein 2 contain a poorly conserved PDZ domain. Results: The crystal structures for the PDZ domains were determined. Conclusion: Both PDZ domains form intertwined domain-swapped homodimers. Significance: The structures have implications for the organization of complexes involving the periaxin/AHNAK family. Periaxin (PRX) is an abundant protein in the peripheral nervous system, with an important role in myelination. PRX participates in large molecular complexes, most likely through the interactions of its N-terminal PSD-95/Discs-large/ZO-1 (PDZ)-like domain. We present the crystal structures of the PDZ-like domains from PRX and its homologue AHNAK nucleoprotein 2 (AHNAK2). The unique intertwined, domain-swapped dimers provide a structural basis for the homodimerization of both proteins. The core of the homodimer is formed by a 6-stranded antiparallel sheet, with every other strand from a different chain. The AHNAK2 PDZ domain structure contains a bound class III ligand peptide. The binding pocket is preformed, and the peptide-PDZ interactions have unique aspects, including two salt bridges and weak recognition of the peptide C terminus. Tight homodimerization may be central to the scaffolding functions of PRX and AHNAK2 in molecular complexes linking the extracellular matrix to the cytoskeletal network.