Structural basis of liprin-α-promoted LAR-RPTP clustering for modulation of phosphatase activity

Nat Commun. 2020 Jan 10;11(1):169. doi: 10.1038/s41467-019-13949-x.

Abstract

Leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) are cell adhesion molecules involved in mediating neuronal development. The binding of LAR-RPTPs to extracellular ligands induces local clustering of LAR-RPTPs to regulate axon growth and synaptogenesis. LAR-RPTPs interact with synaptic liprin-α proteins via the two cytoplasmic phosphatase domains, D1 and D2. Here we solve the crystal structure of LAR_D1D2 in complex with the SAM repeats of liprin-α3, uncovering a conserved two-site binding mode. Cellular analysis shows that liprin-αs robustly promote clustering of LAR in cells by both the liprin-α/LAR interaction and the oligomerization of liprin-α. Structural analysis reveals a unique homophilic interaction of LAR via the catalytically active D1 domains. Disruption of the D1/D1 interaction diminishes the liprin-α-promoted LAR clustering and increases tyrosine dephosphorylation, demonstrating that the phosphatase activity of LAR is negatively regulated by forming clusters. Additionally, we find that the binding of LAR to liprin-α allosterically regulates the liprin-α/liprin-β interaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / physiology
  • Binding Sites
  • COS Cells
  • Cell Adhesion / physiology
  • Chlorocebus aethiops
  • Cluster Analysis
  • Crystallography, X-Ray
  • Ligands
  • Molecular Docking Simulation
  • Mutagenesis, Site-Directed
  • Neurogenesis / physiology*
  • Protein Conformation
  • Protein Interaction Domains and Motifs
  • Receptor-Like Protein Tyrosine Phosphatases, Class 4 / chemistry*
  • Receptor-Like Protein Tyrosine Phosphatases, Class 4 / genetics
  • Receptor-Like Protein Tyrosine Phosphatases, Class 4 / metabolism*
  • Synapses / metabolism

Substances

  • Ligands
  • PTPRA protein, human
  • Receptor-Like Protein Tyrosine Phosphatases, Class 4