Structural basis for interactions between RPTPζ/PTPRZ and the perineuronal net component tenascin‐R

Abstract

Perineuronal nets (PNNs) are complex extracellular matrix structures found exclusively surrounding a subset of neurons in the central nervous system and are established key regulators of developmental neural plasticity and cognitive functions. Unfortunately, our current understanding of the roles that PNNs play in the central nervous system far exceeds our grasp of their molecular architecture. The identities of several PNN components are known and nets include the glycosaminoglycan hyaluronan along with hyaluronan‐binding link proteins, lectican family members, and the extracellular matrix protein tenascin‐R (TNR). Recently, it was shown that disruption of the gene encoding the receptor protein tyrosine phosphatase Ptprz1/RPTPζ altered the appearance of nets from a reticulated structure to puncta on the surface of cortical neuron bodies in adult mice. The structural alterations found in adult ptprz1‐/‐ mice mirror those found in tnr‐/‐ mice, and TNR is absent from the net structures that form in dissociated cultures of ptprz1‐/‐cortical neurons. These findings raise the possibility that TNR and RPTPζ cooperate to promote the assembly of PNNs. Here, we show that TNR associates directly with a fibronectin type III domain in the extracellular region of RPTPζ and provide a structural basis for the interactions between TNR and RPTPζ. Furthermore, we show that mutating residues at the TNR/RPTPζ interface impairs the formation of PNNs in neuronal cultures. Overall, this work sets the stage for analyzing the roles of protein‐protein interactions that underpin the formation of nets.