Crystal Structure of KA2-Subtype Ionotropic Glutamate Receptor Amino Terminal Domain

Abstract

The glutamate receptor ion channels that mediate excitatory synaptic transmission in the mammalian brain have a unique modular architecture distinct from that for other ligand gated ion channels. It took ten years since publication of the first crystal structure of an isolated ligand-binding domain (S1S2) (1) to solve structures of the amino terminal domain (ATD) of GluR6 (2) and GluR2 (3). These structures give insight into the regulation of subtype specific assembly by ATDs. However, structures of ATDs from other subtypes are still unknown. We have now determined high-resolution crystal structures of KA2 ATD in 2 forms at 1.4 A & 1.6 A respectively. KA2ATD has a clamshell-like fold similar to GluR6 and GluR2. However, the dimer assembly is significantly different than that for GluR6 & GluR2 where the R1 & R2 domains of both the protomers contribute equally to dimer formation. In KA2, the R2 domains also co-assemble and form close contacts similar to GluR6 & GluR2 ATDs but the R1 domains are separated. This assembly is interesting because the R1 domain has loops that likely specify subtype specific assembly. These loops make no contacts across the dimer interface in KA2 ATD, consistent with obligate co-assembly of KA2 with GluR5-7 for formation of functional ion channels.References(1) Armstrong, N., Sun, Y., Chen, G.Q. & Gouaux, E. Structure of a glutamate-receptor ligand-binding core in complex with kainate. Nature 395, 913-917 (1998).(2)Kumar J, Schuck P, Jin R, Mayer ML (2009) The N-terminal domain of GluR6-subtype glutamate receptor ion channels. Nat Struct Mol Biol. 16, 631 - 638.(3) Jin R, Singh SK, Gu S, Furukawa H, Sobolevsky AI, Zhou J, Jin Y, Gouaux E (2009) Crystal structure and association behaviour of the GluR2 amino-terminal domain. EMBO J. 28(12):1812-23.