Structure of transmembrane AMPA receptor regulatory protein subunit γ2

• Published in: Nature communications 2025-01, Vol.16 (1), p.671, Article 671
• Main Authors: Hale, W. Dylan, Romero, Alejandra Montaño, Koylass, Nicholas, Warrick, Collin R., Qiu, Zhaozhu, Huganir, Richard L., Twomey, Edward C.
• Format: Article
• Language: English
• Subjects: 101/28; 631/45/269/1149; 631/535/1258/1259; 9/74; Electron microscopy; Electrophysiology; Glutamate receptors; Humanities and Social Sciences; multidisciplinary; Neurotransmission; Protein structure; Proteins; Receptor mechanisms; Receptors; Regulatory proteins; Science; Science (multidisciplinary); Structure-function relationships; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-025-56027-1

Transmembrane AMPA receptor regulatory proteins (TARPs) are claudin-like proteins that tightly regulate AMPA receptors (AMPARs) and are fundamental for excitatory neurotransmission. With cryo-electron microscopy (cryo-EM) we reconstruct the 36 kDa TARP subunit γ2 to 2.3 Å, which points to structural diversity among TARPs. Our data reveals critical motifs that distinguish TARPs from claudins and define how sequence variations within TARPs differentiate subfamilies and their regulation of AMPARs. TARPs are tetraspanins that are claudin-like but regulate glutamate receptors. Here, the moieties that define TARP function and distinguish them from claudins are uncovered through cryo-EM, structure prediction, and electrophysiology.