A model for regulation by SynGAP-α1 of binding of synaptic proteins to PDZ-domain 'Slots' in the postsynaptic density.
SynGAP is a Ras/Rap GTPase-activating protein (GAP) that is a major constituent of postsynaptic densities (PSDs) from mammalian forebrain. Its α1 isoform binds to all three PDZ (PSD-95, Discs-large, ZO-1) domains of PSD-95, the principal PSD scaffold, and can occupy as many as 15% of these PDZ domains. We present evidence that synGAP-α1 regulates the composition of the PSD by restricting binding to the PDZ domains of PSD-95. We show that phosphorylation by Ca2+/calmodulin-dependent protein kinase II (CaMKII) and Polo-like kinase-2 (PLK2) decreases its affinity for the PDZ domains by several fold, which would free PDZ domains for occupancy by other proteins. Finally, we show that three critical postsynaptic signaling proteins that bind to the PDZ domains of PSD-95 are present in higher concentration in PSDs isolated from mice with a heterozygous deletion of synGAP.
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.
Ward G
WG
Walkup
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.
Tara L
TL
Mastro
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.
Leslie T
LT
Schenker
Beckman Institute Protein Expression Center, California Institute of Technology, Pasadena, United States.
Jost
J
Vielmetter
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.
Rebecca
R
Hu
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.
Ariella
A
Iancu
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.
Meera
M
Reghunathan
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.
Barry Dylan
BD
Bannon
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.
Mary B
0000-0003-1369-0525
MB
Kennedy
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein / Q000378:metabolism*; D051379:Mice; D054731:PDZ Domains; D010766:Phosphorylation; D057907:Post-Synaptic Density / Q000737:chemistry*; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020703:ras GTPase-Activating Proteins / Q000378:metabolism*
D000076122:Disks Large Homolog 4 Protein; C484512:Syngap1 protein, mouse; D020703:ras GTPase-Activating Proteins; D017346:Protein Serine-Threonine Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C444640:serum-inducible kinase
CaMKII; SynGAP haploinsufficiency; biochemistry; mouse; neuroscience; synaptic plasticity