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Title: Structure and Assembly Mechanism for Heteromeric Kainate Receptors

Abstract

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 GluR57. 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{sub d} 11 nM, 32,000-fold lower than the K{sub 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.

Authors:
; ;  [1]
  1. (NIH)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
OTHERNIH
OSTI Identifier:
1046237
Resource Type:
Journal Article
Journal Name:
Neuron
Additional Journal Information:
Journal Volume: 71; Journal Issue: (2) ; 07, 2011; Journal ID: ISSN 0896-6273
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; BIOSYNTHESIS; CRYSTAL STRUCTURE; DIMERS; GENES; INTERACTIONS; IONS; MUTANTS; RECEPTORS

Citation Formats

Kumar, Janesh, Schuck, Peter, and Mayer, Mark L. Structure and Assembly Mechanism for Heteromeric Kainate Receptors. United States: N. p., 2012. Web. doi:10.1016/j.neuron.2011.05.038.
Kumar, Janesh, Schuck, Peter, & Mayer, Mark L. Structure and Assembly Mechanism for Heteromeric Kainate Receptors. United States. doi:10.1016/j.neuron.2011.05.038.
Kumar, Janesh, Schuck, Peter, and Mayer, Mark L. Thu . "Structure and Assembly Mechanism for Heteromeric Kainate Receptors". United States. doi:10.1016/j.neuron.2011.05.038.
@article{osti_1046237,
title = {Structure and Assembly Mechanism for Heteromeric Kainate Receptors},
author = {Kumar, Janesh and Schuck, Peter and Mayer, Mark L.},
abstractNote = {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 GluR57. 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{sub d} 11 nM, 32,000-fold lower than the K{sub 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.},
doi = {10.1016/j.neuron.2011.05.038},
journal = {Neuron},
issn = {0896-6273},
number = (2) ; 07, 2011,
volume = 71,
place = {United States},
year = {2012},
month = {10}
}