Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-13949-x
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Funding
- National Natural Science Foundation of China [31770791, 31570741, 31870757]
- Natural Science Foundation of Guangdong Province [2016A030312016]
- Science and Technology Planning Project of Guangdong Province [2017B030301018]
- Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Fundamental Research Institutions [2019SHIBS0002]
- Shenzhen Science and Technology Innovation Commission [JCYJ20160229153100269, JCYJ20160301112450474]
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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-alpha 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-alpha 3, uncovering a conserved two-site binding mode. Cellular analysis shows that liprin-as robustly promote clustering of LAR in cells by both the liprin-alpha/LAR interaction and the oligomerization of liprin-alpha. Structural analysis reveals a unique homophilic interaction of LAR via the catalytically active D1 domains. Disruption of the D1/D1 interaction diminishes the liprin-alpha-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-alpha allosterically regulates the liprin-alpha/liprin-beta interaction.
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