Ko Ji Seung, Pramanik Gopal, Um Ji Won, Shim Ji Seon, Lee Dongmin, Kim Kee Hun, Chung Gug-Young, Condomitti Giuseppe, Kim Ho Min, Kim Hyun, de Wit Joris, Park Kang-Sik, Tabuchi Katsuhiko, Ko Jaewon
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea;
Department of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan; National Institute for Physiological Sciences, The Graduate University for Advanced Studies, Okazaki 444-8787, Japan;
Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1874-9. doi: 10.1073/pnas.1410138112. Epub 2015 Jan 26.
Leukocyte common antigen-related receptor protein tyrosine phosphatases--comprising LAR, PTPδ, and PTPσ--are synaptic adhesion molecules that organize synapse development. Here, we identify glypican 4 (GPC-4) as a ligand for PTPσ. GPC-4 showed strong (nanomolar) affinity and heparan sulfate (HS)-dependent interaction with the Ig domains of PTPσ. PTPσ bound only to proteolytically cleaved GPC-4 and formed additional complex with leucine-rich repeat transmembrane protein 4 (LRRTM4) in rat brains. Moreover, single knockdown (KD) of PTPσ, but not LAR, in cultured neurons significantly reduced the synaptogenic activity of LRRTM4, a postsynaptic ligand of GPC-4, in heterologous synapse-formation assays. Finally, PTPσ KD dramatically decreased both the frequency and amplitude of excitatory synaptic transmission. This effect was reversed by wild-type PTPσ, but not by a HS-binding-defective PTPσ mutant. Our results collectively suggest that presynaptic PTPσ, together with GPC-4, acts in a HS-dependent manner to maintain excitatory synapse development and function.
白细胞共同抗原相关受体蛋白酪氨酸磷酸酶（包括LAR、PTPδ和PTPσ）是组织突触发育的突触粘附分子。在此，我们鉴定出磷脂酰肌醇蛋白聚糖4（GPC - 4）是PTPσ的一种配体。GPC - 4与PTPσ的免疫球蛋白结构域表现出强烈的（纳摩尔级）亲和力以及硫酸乙酰肝素（HS）依赖性相互作用。在大鼠脑中，PTPσ仅与蛋白水解切割后的GPC - 4结合，并与富含亮氨酸重复跨膜蛋白4（LRRTM4）形成额外的复合物。此外，在异源突触形成试验中，在培养的神经元中单独敲低（KD）PTPσ而非LAR，会显著降低GPC - 4的突触后配体LRRTM4的突触生成活性。最后，PTPσ基因敲除显著降低了兴奋性突触传递的频率和幅度。野生型PTPσ可逆转这种效应，但硫酸乙酰肝素结合缺陷型PTPσ突变体则不能。我们的研究结果共同表明，突触前PTPσ与GPC - 4一起，以硫酸乙酰肝素依赖性方式维持兴奋性突触的发育和功能。
