Neuron 2015 Apr 2;86(2):475-89. Epub 2015 Apr 2.
University of Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, 33000 Bordeaux, France; CNRS, Interdisciplinary Institute for Neuroscience, UMR 5297, 33000 Bordeaux, France; Bordeaux Imaging Center, UMS 3420 CNRS, US4 INSERM, University of Bordeaux, 33000 Bordeaux, France. Electronic address:
PSD-95 is a prominent organizer of the postsynaptic density (PSD) that can present a filamentous orientation perpendicular to the plasma membrane. Interactions between PSD-95 and transmembrane proteins might be particularly sensitive to this orientation, as "long" cytoplasmic tails might be required to reach deeper PSD-95 domains. Extension/retraction of transmembrane protein C-tails offer a new way of regulating binding to PSD-95. Using stargazin as a model, we found that enhancing the apparent length of stargazin C-tail through phosphorylation or by an artificial linker was sufficient to potentiate binding to PSD-95, AMPAR anchoring, and synaptic transmission. A linear extension of stargazin C-tail facilitates binding to PSD-95 by preferentially engaging interaction with the farthest located PDZ domains regarding to the plasma membrane, which present a greater affinity for the stargazin PDZ-domain-binding motif. Our study reveals that the concerted orientation of the stargazin C-tail and PSD-95 is a major determinant of synaptic strength.