1. Academic Validation
  2. Structural basis of liprin-α-promoted LAR-RPTP clustering for modulation of phosphatase activity

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.
Xingqiao Xie 1 2 Ling Luo 1 Mingfu Liang 1 Wenchao Zhang 1 Ting Zhang 1 2 Cong Yu 1 3 Zhiyi Wei 4 5
Affiliations

Affiliations

  • 1 Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China.
  • 2 Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China.
  • 3 Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, and Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, Guangdong, 518055, China.
  • 4 Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China. [email protected].
  • 5 Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China. [email protected].
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.

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