Structure and Assembly Mechanism for Heteromeric Kainate Receptors

Laboratory of Cellular and Molecular Neurophysiology, Porter Neuroscience Research Center, NICHD, NIH, DHHS, Bethesda, MD 20892, USA.
Neuron (Impact Factor: 15.05). 07/2011; 71(2):319-31. DOI: 10.1016/j.neuron.2011.05.038
Source: PubMed


Native glutamate receptor ion channels are tetrameric assemblies containing two or more different subunits. NMDA receptors are obligate heteromers formed by coassembly of two or three divergent gene families. While some AMPA and kainate receptors can form functional homomeric ion channels, the KA1 and KA2 subunits are obligate heteromers which function only in combination with GluR5-7. The mechanisms controlling glutamate receptor assembly involve an initial step in which the amino terminal domains (ATD) assemble as dimers. Here, we establish by sedimentation velocity that the ATDs of GluR6 and KA2 coassemble as a heterodimer of K(d) 11 nM, 32,000-fold lower than the K(d) for homodimer formation by KA2; we solve crystal structures for the GluR6/KA2 ATD heterodimer and heterotetramer assemblies. Using these structures as a guide, we perform a mutant cycle analysis to probe the energetics of assembly and show that high-affinity ATD interactions are required for biosynthesis of functional heteromeric receptors.

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    • "To simulate a heteromer having a 2:2 stoichiometry, as is the case for GluK2/GluK5 KARs (Reiner et al. 2012), prolineswere introduced into the equivalent α-helical positions of the NaK structure on opposing subunits (i.e. A and C), in agreement with prior work on KAR heteromers (Kumar et al. 2011). Changes in cross-pore distances between the centre of mass of the α-carbons of residues 50–53 in opposing subunits are summarized in Fig. 6D. "
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