Structure of the FERM domain of a neural scaffold protein FRMPD4 implicated in X-linked intellectual disability. Issue 23 (11th December 2020)

• Record Type: Journal Article
• Authors: Wang, Mengli; Lin, Lin; Shi, Yingdong; He, Liping; Wang, Chao; Zhu, Jinwei
• Is Part Of: Biochemical journal. Volume 477:Issue 23(2020)
• Page Start: 4623
• Page End: 4634
• Publication Date: 2020-12-11
• Subjects: crystal structure -- FERM domain -- FRMPD4 -- X-linked intellectual disability; Biochemistry -- Periodicals; 572
• DOI: 10.1042/BCJ20200857
• Languages: English
• ISSNs: 0264-6021

Abstract

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 the biological function of FRMPD4 by destabilizing the FERM structure.