Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA; Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555, USA.
Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA; Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555, USA.
Structure. 2021 Jul 1;29(7):664-678.e6. doi: 10.1016/j.str.2021.01.003. Epub 2021 Feb 2.
Hevin is secreted by astrocytes and its synaptogenic effects are antagonized by the related protein, SPARC. Hevin stabilizes neurexin-neuroligin transsynaptic bridges in vivo. A third protein, membrane-tethered MDGA, blocks these bridges. Here, we reveal the molecular underpinnings of a regulatory network formed by this trio of proteins. The hevin FS-EC structure differs from SPARC, in that the EC domain appears rearranged around a conserved core. The FS domain is structurally conserved and it houses nanomolar affinity binding sites for neurexin and neuroligin. SPARC also binds neurexin and neuroligin, competing with hevin, so its antagonist action is rooted in its shortened N-terminal region. Strikingly, the hevin FS domain competes with MDGA for an overlapping binding site on neuroligin, while the hevin EC domain binds the extracellular matrix protein collagen (like SPARC), so that this trio of proteins can regulate neurexin-neuroligin transsynaptic bridges and also extracellular matrix interactions, impacting synapse formation and ultimately neural circuits.
Hevin 由星形胶质细胞分泌，其促突触生成作用受到相关蛋白 SPARC 的拮抗。Hevin 在体内稳定神经连接蛋白-神经黏附素突触间桥。第三种蛋白膜锚定蛋白 MDGA 阻断这些桥。在此，我们揭示了由这三种蛋白组成的调控网络的分子基础。Hevin FS-EC 结构与 SPARC 不同，EC 结构域似乎围绕保守核心重新排列。FS 结构域结构保守，具有对神经连接蛋白和神经黏附素的纳摩尔亲和力结合位点。SPARC 也与神经连接蛋白和神经黏附素结合，与 Hevin 竞争，因此其拮抗剂作用源于其缩短的 N 端区域。引人注目的是，Hevin FS 结构域与 MDGA 竞争神经黏附素上的重叠结合位点，而 Hevin EC 结构域与细胞外基质蛋白胶原结合（与 SPARC 一样），因此这三种蛋白可以调节神经连接蛋白-神经黏附素突触间桥和细胞外基质相互作用，影响突触形成，最终影响神经回路。
