Structure of the FERM domain of a neural scaffold protein FRMPD4 implicated in X-linked intellectual disability

Abstract

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.

Preso enhances mGluR1-mediated excitotoxicity by modulating the phosphorylation of mGluR1-Homer1 complex and facilitating an ER stress after traumatic brain injury

“…Because Preso has a binding site for group I mGluRs in its FERM domain [ 16 ], the interaction between Preso and group I mGluRs is significantly suppressed after deletion of the FERM domain [ 18 , 19 ]. Furthermore, the mGluR1 C-terminus has a predicted binding site for the FERM domain [ 27 ].…”

“…Preso (PSD-95-interacting regulator of spine morphogenesis or Preso1) is a scaffolding protein comprising WW, PDZ and FERM domains at the N terminus, a Homer-binding motif (HBM) and a PDZ-binding motif (PBM) at the C terminus, and is therefore also called FERM and PDZ domain containing 4 (FRMPD4) [ 15 , 16 ]. Preso facilitates NMDAR signaling during glutamate-induced excitotoxicity by interacting with PSD-95 [ 17 ].…”

“…In addition to NMDAR, Preso regulates mGluR function, including mGluR-associated excitotoxicity [ 17 , 18 ]. Remarkably, Preso binds to group I mGluRs through its FERM domain and also couples with Homer1 via its HBM [ 16 ]. Through these interactions, Preso coordinates the coupling of mGluR5 with Homer1 and thus promotes mGluR5-mediated pain signaling [ 18 ].…”

The Complex Formed by Group I Metabotropic Glutamate Receptor (mGluR) and Homer1a Plays a Central Role in Metaplasticity and Homeostatic Synaptic Scaling

“…Group I mGluR and PDK are first assembled by an anchoring protein called FRMPD4/Preso1 forming a microdomain. FRMPD4/Preso1 is a multidomain protein containing a FERM domain that binds cytoplasmic tails of Group I mGluR, an Homer binding domain and a Cterminal PDZ-binding-ligand that interacts with PSD-95 (Hu et al, 2012;Lee et al, 2008;Wang et al, 2020). FRMPD4/Preso1 is crucial for the formation of excitatory synapses and dendritic spines and for physiological regulation of synaptic mGluR (Lee et al, 2008).…”

“…These bidirectional activity-dependent modifications of excitatory synaptic strength are essential for learning and storage of new memories. NMDA receptor activation is required for these forms of plasticity (Huganir and Nicoll, 2013), but Group I mGluR are also implicated, via different molecular mechanisms, in both LTD (Luscher and Huber, 2010) and LTP (Wang et al, 2020). Changes in synaptic activity also occur over longer timescales and are called "non-Hebbian neuronal plasticity".…”