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 biological function of FRMPD4 by destabilizing the FERM structure.

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