Periaxin and AHNAK Nucleoprotein 2 Form Intertwined Homodimers through Domain Swapping

Petri Kursula,Huijong Han

doi:10.1074/jbc.m114.554816

Abstract

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 β 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.

Highlights

Periaxin and AHNAK nucleoprotein 2 contain a poorly conserved PDZ domain
Lys176 and Lys139 correspond to Arg82 and Arg45 in the PRX. Both PRX and the AHNAK proteins participate in large protein complexes at the plasma membrane, linking the extracellular matrix to the cytoskeleton
We provide here a structural basis for the PDZ domain, implying that similar salt bridge interactions dimeric assembly of PRX/AHNAK, and the surprising inter

Summary

Background

Periaxin and AHNAK nucleoprotein 2 contain a poorly conserved PDZ domain. Results: The crystal structures for the PDZ domains were determined. The unique intertwined, domain-swapped dimers provide a structural basis for the homodimerization of both proteins. S-PRX is uniformly distributed in the cytoplasm and the nucleus of the Schwann cell, and a function for S-PRX in regulating mRNA splicing has been suggested [12] Both PRX isoforms share their 127 N-terminal residues, including a predicted PDZ domain [13]. Intertwined Dimerization of PDZ Domains form a unique subfamily of PDZ proteins that are likely to have similar functions in complexes linking the extracellular matrix to the cytoskeleton [12]. We report the first crystal structures for PRX and AHNAK2 Their PDZ domains exhibit uniquely intertwined dimers, with extensive three-dimensional domain swapping. Based on strong interactions in the crystal state, similar dimerization of both proteins is likely to occur in vivo

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION