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SALM5诱导PTPδ二聚化促进突触分化的结构基础。

Structural basis of SALM5-induced PTPδ dimerization for synaptic differentiation.

作者信息

Lin Zhaohan, Liu Jianmei, Ding Huandi, Xu Fei, Liu Heli

机构信息

State Key Laboratory of Natural and Biomimetic Drugs & Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100191, China.

出版信息

Nat Commun. 2018 Jan 18;9(1):268. doi: 10.1038/s41467-017-02414-2.

DOI:10.1038/s41467-017-02414-2
PMID:29348579
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5773555/
Abstract

SALM5, a synaptic adhesion molecule implicated in autism, induces presynaptic differentiation through binding to the LAR family receptor protein tyrosine phosphatases (LAR-RPTPs) that have been highlighted as presynaptic hubs for synapse formation. The mechanisms underlying SALM5/LAR-RPTP interaction remain unsolved. Here we report crystal structures of human SALM5 LRR-Ig alone and in complex with human PTPδ Ig1-3 (MeA). Distinct from other LAR-RPTP ligands, SALM5 mainly exists as a dimer with LRR domains from two protomers packed in an antiparallel fashion. In the 2:2 heterotetrameric SALM5/PTPδ complex, a SALM5 dimer bridges two separate PTPδ molecules. Structure-guided mutations and heterologous synapse formation assays demonstrate that dimerization of SALM5 is prerequisite for its functionality in inducing synaptic differentiation. This study presents a structural template for the SALM family and reveals a mechanism for how a synaptic adhesion molecule directly induces cis-dimerization of LAR-RPTPs into higher-order signaling assembly.

摘要

SALM5是一种与自闭症相关的突触粘附分子，它通过与LAR家族受体蛋白酪氨酸磷酸酶（LAR-RPTPs）结合来诱导突触前分化，而LAR-RPTPs已被视为突触形成的突触前枢纽。SALM5/LAR-RPTP相互作用的潜在机制仍未解决。在此，我们报告了人SALM5 LRR-Ig单独以及与人PTPδ Ig1-3（MeA）形成复合物时的晶体结构。与其他LAR-RPTP配体不同，SALM5主要以二聚体形式存在，两个原体的LRR结构域以反平行方式堆积。在2:2异源四聚体SALM5/PTPδ复合物中，一个SALM5二聚体连接两个独立的PTPδ分子。结构导向的突变和异源突触形成试验表明，SALM5的二聚化是其诱导突触分化功能的先决条件。本研究为SALM家族提供了一个结构模板，并揭示了一种突触粘附分子如何直接诱导LAR-RPTPs顺式二聚化形成高阶信号组装的机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3d3/5773555/fa4f2f3dbfee/41467_2017_2414_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3d3/5773555/d4d03ee51a9c/41467_2017_2414_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3d3/5773555/ffd43039156c/41467_2017_2414_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3d3/5773555/e0cd0851d47b/41467_2017_2414_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3d3/5773555/664263bd7f83/41467_2017_2414_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3d3/5773555/bbaa33187a36/41467_2017_2414_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3d3/5773555/fa4f2f3dbfee/41467_2017_2414_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3d3/5773555/d4d03ee51a9c/41467_2017_2414_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3d3/5773555/ffd43039156c/41467_2017_2414_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3d3/5773555/e0cd0851d47b/41467_2017_2414_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3d3/5773555/664263bd7f83/41467_2017_2414_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3d3/5773555/bbaa33187a36/41467_2017_2414_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3d3/5773555/fa4f2f3dbfee/41467_2017_2414_Fig6_HTML.jpg

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