Lin Eric I.

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Lin
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Eric I.
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  • Article
    CASK regulates SAP97 conformation and its interactions with AMPA and NMDA receptors
    (Society for Neuroscience, 2013-07-17) Lin, Eric I. ; Jeyifous, Okunola ; Green, William N.
    SAP97 interacts with AMPA receptors (AMPARs) and NMDA receptors (NMDARs) during sorting and trafficking to synapses. Here we addressed how SAP97 distinguishes between AMPARs and NMDARs and what role the adaptor/scaffold protein, CASK, plays in the process. Using intramolecular SAP97 Förster resonance energy transfer sensors, we demonstrated that SAP97 is in “extended” or “compact” conformations in vivo. SAP97 conformation was regulated by a direct interaction between SAP97 and CASK through L27 protein-interaction domains on each protein. Unbound SAP97 was mostly in the compact conformation, while CASK binding stabilized it in an extended conformation. In HEK cells and rat hippocampal neurons, SAP97 in the compact conformation preferentially associated and colocalized with GluA1-containing AMPARs, and in the extended conformation colocalized with GluN2B-containing NMDARs. Altogether, our findings suggest a molecular mechanism by which CASK binding regulates SAP97 conformation and its subsequent sorting and synaptic targeting of AMPARs and NMDARs during trafficking to synapses.
  • Preprint
    Palmitoylation regulates glutamate receptor distributions in postsynaptic densities through control of PSD95 conformation and orientation
    ( 2016-08) Jeyifous, Okunola ; Lin, Eric I. ; Chen, Xiaobing ; Antinone, Sarah E. ; Mastro, Ryan ; Drisdel, Renaldo ; Reese, Thomas S. ; Green, William N.
    PSD95 and SAP97 are homologous scaffold proteins with different N-terminal domains, possessing either a palmitoylation site (PSD95) or an L27 domain (SAP97). Here, we measured PSD95 and SAP97 conformation in vitro and in postsynaptic densities (PSDs) using FRET and electron microscopy, and examined how conformation regulated interactions with AMPA-type and NMDAtype glutamate receptors (AMPARs/NMDARs). Palmitoylation of PSD95 changed its conformation from a compact to an extended configuration. PSD95 associated with AMPARs (via TARP subunits) or NMDARs (via GluN2B subunits) only in its palmitoylated and extended conformation. In contrast, SAP97 in its extended conformation associates with NMDARs but not with AMPARs. Within PSDs, PSD95 and SAP97 were largely in the extended conformation, but had different orientations. PSD95 oriented perpendicular to the PSD membrane, with its palmitoylated, N-terminal domain at the membrane. SAP97 oriented parallel to the PSD membrane, likely as a dimer through interactions of its N-terminal, L27 domain. Changing PSD95 palmitoylation in PSDs altered PSD95 and AMPAR levels but did not affect NMDAR levels. These results indicate that in PSDs, PSD95 palmitoylation, conformation and its interactions are dynamic when associated with AMPARs, and more stable when associated with NMDARs. Altogether, our results are consistent with differential regulation of PSD95 palmitoylation in PSDs resulting from the clustering of palmitoylating and depalmitoylating enzymes into AMPAR nanodomains segregated away from NMDAR nanodomains.