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

2020 ◽  
Vol 477 (23) ◽  
pp. 4623-4634
Author(s):  
Mengli Wang ◽  
Lin Lin ◽  
Yingdong Shi ◽  
Liping He ◽  
Chao Wang ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Metabotropic Glutamate Receptors ◽  
Binding Mode ◽  
Scaffold Protein ◽  
Excitatory Synapses ◽  
Basic Residue ◽  
Ferm Domain ◽  
Metabotropic Glutamate ◽  
Binding Groove ◽  
Target Binding

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.

scholarly journals Stabilization of spine Synaptopodin by mGluR1 is required for mGluR-LTD

2021 ◽  
Author(s):  
Luisa Speranza ◽  
Yanis Inglebert ◽  
Claudia De Sanctis ◽  
Pei You Wu ◽  
Magdalena Kalinowska ◽  
...  
Keyword(s):  
Metabotropic Glutamate Receptors ◽  
De Novo ◽  
Smooth Endoplasmic Reticulum ◽  
Excitatory Synapses ◽  
Metabotropic Glutamate ◽  
Selective Preservation ◽  
Mushroom Spines ◽  
Activity Dependent

Dendritic spines, actin-rich protrusions forming the postsynaptic sites of excitatory synapses, undergo activity-dependent molecular and structural remodeling. Activation of group 1 metabotropic glutamate receptors - mGluR1 and mGluR5 - by synaptic or pharmacological stimulation, induces LTD but whether this is accompanied with spine elimination remains unresolved. A subset of telencephalic mushroom spines contains the spine apparatus (SA), an enigmatic organelle composed of stacks of smooth endoplasmic reticulum, whose formation depends on the expression of the actin-bundling protein Synaptopodin. Allocation of Synaptopodin to spines appears governed by cell-intrinsic mechanisms as the relative frequency of spines harboring Synaptopodin is conserved in vivo and in vitro. Here we show that expression of Synaptopodin/SA in spines is required for induction of mGluR-LTD at Schaffer collateral-CA1 synapses. Post-mGluR-LTD, mushroom spines lacking Synaptopodin/SA are selectively lost whereas spines harboring it are preserved, a process dependent on activation of mGluR1 but not mGluR5. Mechanistically, we find that mGluR1 supports physical retention of Synaptopodin within excitatory spine synapses during LTD while triggering lysosome-dependent degradation of the protein residing in dendritic shafts. Together, these results reveal a cellular mechanism, dependent on mGluR1, which enables selective preservation of stronger spines containing Synaptopodin/SA while eliminating weaker ones and potentially countering spurious strengthening by de novo recruitment of Synaptopodin. Overall our results identify spines with Synaptopodin/SA as the locus of mGluR-LTD and underscore the importance of the molecular microanatomy of spines in synaptic plasticity.

scholarly journals Essential regulatory functions of CaMKII T286 phosphorylation in LTP and two distinct forms of LTD

2022 ◽  
Author(s):  
K. Ulrich Bayer ◽  
Sarah G Cook ◽  
Nicole L Rumian
Keyword(s):  
Glutamate Receptors ◽  
Hippocampal Neurons ◽  
Metabotropic Glutamate Receptors ◽  
Long Term Potentiation ◽  
Inhibitory Synapses ◽  
Excitatory Synapses ◽  
Metabotropic Glutamate ◽  
Term Potentiation ◽  
Dependent Protein ◽  
Regulatory Functions

The Ca2+/calmodulin-dependent protein kinase II (CaMKII) mediates both long-term potentiation and depression (LTP and LTD) of excitatory synapses, two opposing forms of synaptic plasticity induced by strong versus weak stimulation of NMDA-type glutamate receptors (NMDARs). NMDAR-dependent LTD is prevalent in juvenile hippocampus, but in mature hippocampus, LTD is still readily induced by stimulating metabotropic glutamate receptors (mGluRs). Here we show that mGluR-dependent LTD also requires CaMKII and its T286 autophosphorylation that induces Ca2+-independent autonomous kinase activity. This autophosphorylation (i) accelerated CaMKII movement to excitatory synapses after LTP stimuli and (ii) was required for the movement to inhibitory synapses after NMDAR-LTD stimuli. Similar to NMDAR-LTD, the mGluR-LTD stimuli did not induce any CaMKII movement to excitatory synapses. However, in contrast to NMDAR-LTD, the mGluR-LTD did not involve CaMKII movement to inhibitory synapses and did not require additional T305/306 autophosphorylation. Taken together, even though CaMKII T286 autophosphorylation has a longstanding prominent role in LTP, it is also required for both major forms of LTD in hippocampal neurons, albeit with differential requirements for the heterosynaptic communication of excitatory signals to inhibitory synapses.

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