The STEP61 interactome reveals subunit-specific AMPA receptor binding and synaptic regulation.
Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific protein phosphatase that regulates a variety of synaptic proteins, including NMDA receptors (NAMDRs). To better understand STEP's effect on other receptors, we used mass spectrometry to identify the STEP61 interactome. We identified a number of known interactors, but also ones including the GluA2 subunit of AMPA receptors (AMPARs). We show that STEP61 binds to the C termini of GluA2 and GluA3 as well as endogenous AMPARs in hippocampus. The synaptic expression of GluA2 and GluA3 is increased in STEP-KO mouse brain, and STEP knockdown in hippocampal slices increases AMPAR-mediated synaptic currents. Interestingly, STEP61 overexpression reduces the synaptic expression and synaptic currents of both AMPARs and NMDARs. Furthermore, STEP61 regulation of synaptic AMPARs is mediated by lysosomal degradation. Thus, we report a comprehensive list of STEP61 binding partners, including AMPARs, and reveal a central role for STEP61 in differentially organizing synaptic AMPARs and NMDARs.
['Won|Sehoon|S|', 'Incontro|Salvatore|S|', 'Li|Yan|Y|', 'Nicoll|Roger A|RA|', 'Roche|Katherine W|KW|']
D000818:Animals D002853:Chromatography, Liquid D008247:Lysosomes D051379:Mice D010766:Phosphorylation D011485:Protein Binding D017027:Protein Tyrosine Phosphatases D018091:Receptors, AMPA D013569:Synapses D053719:Tandem Mass Spectrometry
AMPA receptor STEP lysosome LC/MS/MS dephosphorylation