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.
Highlights
Leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) are cell adhesion molecules involved in mediating neuronal development
To understand the molecular mechanism underlying the liprin-α/LAR-RPTP interaction, we purified the C-terminal sterile alpha motif (SAM) repeats of liprin-α2 (α2_SAM123) and the cytoplasmic D1 and D2 domains of LAR (LAR_D1D2), which are highly conserved across species (Fig. 1a and Supplementary Figs. 1 and 2)
Since the insertion loop is essential for the binding of liprin-α to calmodulin-dependent serine protein kinase (CASK), our observation demonstrates that liprin-α may interact with LAR and CASK by using different surfaces on SAM123
Summary
Leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) are cell adhesion molecules involved in mediating neuronal development. 1234567890():,; The leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs), named as Type IIα RPTPs, are cell surface receptors important for the developing nervous system[1,2,3]. By participating in both cell–cell and cell–extracellular matrix (ECM) adhesions, LAR-RPTPs play critical roles in mediating axon guidance, neurite outgrowth, as well as synapse formation and differentiation[4,5,6,7,8]. The binding surfaces of LAR and liprin-β on liprin-α_SAM123 do not overlap with each other, LAR can compete with the binding of liprin-β to liprin-α through an allosteric way
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