Distinct Structural Pathways Coordinate the Activation of AMPA Receptor-Auxiliary Subunit Complexes

Dawe, G. Brent; Musgaard, Maria; Aurousseau, Mark; Nayeem, Naushaba; Green, Tim; Biggin, Philip C.; Bowie, Derek

doi:10.1016/j.neuron.2016.01.038

Cited by 64 publications

(77 citation statements)

References 57 publications

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“…Confirming a key role of the electrostatic interactions in regulation of AMPAR function by STZ, recent mutagenesis experiments on a similar GluA2-STZ tandem construct showed that the aspartate substitution of a KGK motif, which is highly conserved in AMPARs and includes K697 and K699 residues in the helix H-β strand 10 loop, almost completely abolished the effects of STZ on GluA2 receptor function (29). In addition, the electronegative motif in the STZ β4-TM2 loop is highly conserved across type I TARPs (19), including γ2 (STZ), γ3, γ4, and γ8 (fig.…”

mentioning

confidence: 91%

Elucidation of AMPA receptor–stargazin complexes by cryo–electron microscopy

Twomey

Yelshanskaya

Grassucci

et al. 2016

Science

122

189

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AMPA-subtype ionotropic glutamate receptors (AMPARs) mediate fast excitatory neurotransmission, and contribute to high cognitive processes such as learning and memory. In the brain, AMPAR trafficking, gating, and pharmacology is tightly controlled by transmembrane AMPAR regulatory proteins (TARPs). Here, we used cryo-EM to elucidate the structural basis of AMPAR regulation by one of these auxiliary proteins, TARP γ2 or stargazin (STZ). Our structures illuminate the variable interaction stoichiometry of the AMPAR-TARP complex, with one or two TARP molecules binding one tetrameric AMPAR. Analysis of the AMPAR-STZ binding interfaces suggests that electrostatic interactions between the extracellular domains of AMPAR and STZ play an important role in modulating AMPAR function through contact surfaces that are conserved across AMPARs and TARPs. We propose a model explaining how TARPs stabilize the activated state of AMPARs and how the interactions between AMPARs and their auxiliary proteins control fast excitatory synaptic transmission.

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mentioning

confidence: 91%

Elucidation of AMPA receptor–stargazin complexes by cryo–electron microscopy

Twomey

Yelshanskaya

Grassucci

et al. 2016

Science

122

189

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“…While structural details on the AMPAR core have been known, insights into the structures of AMPARs bound to their auxiliary subunits are just beginning to emerge. As shown in two separate cryo-EM studies (Twomey et al, 2016; Zhao et al, 2016), the transmembrane AMPAR regulatory protein (TARP) γ2 or stargazin (STZ), which positively modulates AMPAR trafficking, agonist efficacy, and favors the open-state of the channel (Chen et al, 2000; MacLean et al, 2014; Priel et al, 2005; Tomita et al, 2005; Zhang et al, 2014), assembles with AMPAR through its TMD and extracellular loops that reach to the AMPAR LBD to modulate gating kinetics (Dawe et al, 2016; Tomita et al, 2005), at variable stoichiometry. While these studies provided important insight into the assembly of native AMPAR complexes in the closed state, the modest resolution of the corresponding cryo-EM reconstructions prevented detailed understanding of AMPAR auxiliary subunit assembly, how auxiliary subunits structurally facilitate changes in gating kinetics, and the mechanism by which auxiliary subunits with different function from STZ assemble around the AMPAR core.…”

Section: Introductionmentioning

confidence: 99%

Structural Bases of Desensitization in AMPA Receptor-Auxiliary Subunit Complexes

Twomey

Yelshanskaya

Grassucci

et al. 2017

Neuron

102

161

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SUMMARY Fast excitatory neurotransmission is mediated by AMPA-subtype ionotropic glutamate receptors (AMPARs). AMPARs, localized at post-synaptic densities, are regulated by transmembrane auxiliary subunits that modulate AMPAR assembly, trafficking, gating and pharmacology. Aberrancies in AMPAR-mediated signaling are associated with numerous neurological disorders. Here, we report cryo-EM structures of an AMPAR in complex with the auxiliary subunit GSG1L in the closed and desensitized states. GSG1L favors the AMPAR desensitized state, where channel closure is facilitated by profound structural rearrangements in the AMPAR extracellular domain, with ligand-binding domain dimers losing their local two-fold rotational symmetry. Our structural and functional experiments suggest that AMPAR auxiliary subunits share a modular architecture and use a common transmembrane scaffold for distinct extracellular modules to differentially regulate AMPAR gating. By comparing the AMPAR-GSG1L complex structures, we map conformational changes accompanying AMPAR recovery from desensitization and reveal structural bases for regulation of synaptic transmission by auxiliary subunits.

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“…Nonetheless, a conserved acidic region spanning residues 85-95 (sequence: EDADYEADTAE) is present in the TARP extracellular ‘loops’ adjacent to the α1 helix (Extended Data Fig. 4a), poised to interact with several positively charged residues on the lower lobe of the LBD, including the “KGK” sequence at residues 697-699 of the receptor 28 (Fig. 3b).…”

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confidence: 99%

Architecture of fully occupied GluA2 AMPA receptor–TARP complex elucidated by cryo-EM

Zhao

Chen

Yoshioka

et al. 2016

Nature

110

176

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Fast excitatory neurotransmission in the mammalian central nervous system is largely carried out by AMPA-sensitive ionotropic glutamate receptors. Localized within the postsynaptic density of glutamatergic spines, AMPA receptors are composed of heterotetrameric receptor assemblies associated with auxiliary subunits, the most common of which are transmembrane AMPA-receptor regulatory proteins (TARPs). The association of TARPs with AMPA receptors modulates the kinetics of receptor gating and pharmacology, as well as trafficking. Here we report the cryo-EM structure of the homomeric GluA2 AMPA receptor saturated with TARP γ2 subunits, showing how the TARPs are arranged with four-fold symmetry around the ion channel domain, making extensive interactions with the M1, M2 and M4 TM helices. Poised like partially opened ‘hands’ underneath the two-fold symmetric ligand binding domain (LBD) ‘clamshells’, one pair of TARPs are juxtaposed near the LBD dimer interface, while the other pair is near the LBD dimer-dimer interface. The extracellular ‘domains’ of TARP are positioned to not only modulate LBD ‘clamshell’ closure, but also to affect conformational rearrangements of the LBD layer associated with receptor activation and desensitization, while the TARP transmembrane (TM) domains buttress the ion channel pore.

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Distinct Structural Pathways Coordinate the Activation of AMPA Receptor-Auxiliary Subunit Complexes

Cited by 64 publications

References 57 publications

Elucidation of AMPA receptor–stargazin complexes by cryo–electron microscopy

Elucidation of AMPA receptor–stargazin complexes by cryo–electron microscopy

Structural Bases of Desensitization in AMPA Receptor-Auxiliary Subunit Complexes

Architecture of fully occupied GluA2 AMPA receptor–TARP complex elucidated by cryo-EM

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