Scaffold proteins play crucial roles in orchestrating synaptic signaling and plasticity in the excitatory synapses by providing a structural link between glutamatergic receptors, signaling molecules, and neuronal cytoskeletons. FRMPD4 is a neural scaffold protein that binds to metabotropic glutamate receptors via its FERM domain. Here, we determine the crystal structure of the FERM domain of FRMPD4 at 2.49 Å resolution. The structure reveals that the canonical target binding groove of FRMPD4 FERM is occupied by a conserved fragment C-terminal to the FERM domain, suggesting that the FRMPD4–mGluR interaction may adopt a distinct binding mode. In addition, FRMPD4 FERM does not contain a typical phosphoinositide binding site at the F1/F3 cleft found in ERM family FERM domains, but it possesses a conserved basic residue cluster on the F2 lobe which could bind to lipid effectively. Finally, analysis of mutations that are associated with X-linked intellectual disability suggests that they may compromise the biological function of FRMPD4 by destabilizing the FERM structure.

中文翻译：

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X连锁智力障碍涉及神经支架蛋白FRMPD4的FERM域的结构。

支架蛋白通过提供谷氨酸能受体，信号分子和神经元细胞骨架之间的结构联系，在协调突触信号和兴奋性突触的可塑性中起关键作用。FRMPD4是一种神经支架蛋白，可通过其FERM结构域与代谢型谷氨酸受体结合。在这里，我们以2.49Å的分辨率确定FRMPD4的FERM域的晶体结构。该结构表明，FRMPD4 FERM的经典靶标结合槽被FERM域的C端保守片段占据，这表明FRMPD4–mGluR相互作用可能采用独特的结合模式。此外，FRMPD4 FERM在ERM家族FERM域中的F1 / F3裂口处不包含典型的磷酸肌醇结合位点，但它在F2瓣上具有保守的碱性残基簇，可以有效结合脂质。最后，对与X连锁智力障碍相关的突变的分析表明，它们可能通过破坏FERM结构的稳定性而损害FRMPD4的生物学功能。