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

Xingqiao Xie, Ling Luo, Mingfu Liang, Wenchao Zhang, Ting Zhang, Cong Yu and Zhiyi Wei ()
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Xingqiao Xie: Southern University of Science and Technology
Ling Luo: Southern University of Science and Technology
Mingfu Liang: Southern University of Science and Technology
Wenchao Zhang: Southern University of Science and Technology
Ting Zhang: Southern University of Science and Technology
Cong Yu: Southern University of Science and Technology
Zhiyi Wei: Southern University of Science and Technology

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-13949-x

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