Flap loop of GluD2 binds to Cbln1 and induces presynaptic differentiation
Flap loop of GluD2 binds to Cbln1 and induces presynaptic differentiation
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DOI：
10.1016/j.bbrc.2010.06.114
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发表时间：
2010-07-30
影响因子：
3.1
通讯作者：
Hirano, Tomoo
中科院分区：
文献类型：
--
作者：
Kuroyanagi, Tomoaki;Hirano, Tomoo
谷氨酸受体δ 2（GluD 2）选择性地表达在平行纤维（PF）-浦肯野神经元（PN）突触的突触后棘上。GluD 2敲除小鼠PF-PN突触数量减少，表明GluD 2参与突触形成。最近的研究表明，GluD 2诱导突触前分化的方式依赖于其N-末端结构域（NTD）通过结合Cbln 1分泌的小脑颗粒神经元。然而，NTD与Cbln 1特异性结合的潜在机制仍然难以捉摸。在这里，我们已经确定了皮瓣环（Arg 321-Trp 339）的谷氨酸2（谷氨酸2-NTD）的NTD作为一个关键区域的结合到Cbln 1和诱导突触前分化。在HER细胞中，不表达野生型GluD 2，但在瓣环中具有突变的GluD 2，突触前分化的诱导和Cbln 1的结合都被废除。特别地，Arg 321或Trp 323到丙氨酸的单个氨基酸取代足以使GluD 2功能失效。最后，GluD 2-NTD的同源模型表明，皮瓣环位于远端，这似乎与Cbln 1和突触前静脉曲张的相互作用一致。(C)2010年爱思唯尔公司All rights reserved.
Glutamate receptor delta 2 (GluD2) is selectively expressed on the postsynaptic spines at parallel-fiber (PF)-Purkinje neuron (PN) synapses. GluD2 knockout mice show a reduced number of PF-PN synapses, suggesting that GluD2 is involved in synapse formation. Recent studies revealed that GluD2 induces presynaptic differentiation in a manner dependent on its N-terminal domain (NTD) through binding of Cbln1 secreted from cerebellar granule neurons. However, the underlying mechanism of the specific binding of the NTD to Cbln1 remains elusive. Here, we have identified the flap loop (Arg321-Trp339) in the NTD of GluD2 (GluD2-NTD) as a crucial region for the binding to Cbln1 and the induction of presynaptic differentiation. Both induction of presynaptic differentiation and binding of Cbln1 were abolished in the HER cells expressing not wild-type GluD2 but GluD2 with mutations in the flap loop. Especially, single amino acid substitution of either Arg321 or Trp323 to alanine was sufficient to disable the GluD2 function. Finally, a homology model of GluD2-NTD suggested that the flap loop is located at the distal end, which appears consistent with an interaction with Cbln1 and a presynaptic varicosity. (C) 2010 Elsevier Inc. All rights reserved.