Title : Crystal structures of the glutamate
receptor ion
channel GluK3 and
GluK5 amino-terminal
domains
Abstract :
- Ionotropic glutamate receptors ( iGluRs ) mediate the majority of fast excitatory synaptic neurotransmission in the central nervous system
- The selective assembly of iGluRs into AMPA, kainate, and N-methyl-d- aspartic acid ( NMDA ) receptor subtypes is regulated by thei r extracellula r amino-terminal domains (ATDs)
- Kainate receptors are furthe r classified into low-affinity receptor families ( GluK1- GluK3 ) and high-affinity r eceptor families ( GluK4- GluK5 ) based on thei r affinity fo r the neurotoxin kainic acid
- These two families share a 42% sequence identity fo r the intact receptor but only a 27% sequence identity at the level of ATD
- We have determined fo r the first time the high-resolution crystal structures of GluK3 and GluK5 ATDs, both of which crystallize as dimers but with a strikingly different dime r assembly at the R1 interface
- By contrast, fo r both GluK3 and GluK5 , the R2 domain dime r assembly is simila r to those reported previously fo r othe r non-NMDA iGluRs
- This observation is consistent with the reports that GluK4- GluK5 cannot form functional homomeric ion channels and require obligate coassembly with GluK1- GluK3
- Ou r analysis also reveals that the relative orientation of domains R1 and R2 in individual non-NMDA receptor ATDs varies by up to 10°, in contrast to the 50° difference reported fo r the NMDA receptor GluN2B subunit
- This restricted domain movement in non-NMDA receptor ATDs seems to result both from extensive intramolecula r contacts between domain R1 and domain R2 and from thei r assembly as dimers, which interact at both R1 and R2 domains
- Ou r results provide the first insights into the structure and function of GluK4-G luK5, the least understood family of iGluRs
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