Flexibility of a Glutamate-Binding Domain

Oswald, Robert E.

doi:10.1016/j.str.2007.09.005

Cited by 4 publications

(3 citation statements)

References 13 publications

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“…Studies of the full-length receptor, however, have been primarily focused on the AMPA and NMDA subtypes 9–12,14,15,18 , with only an antagonist- and agonist-bound structure of the full-length kainate receptor. The structures 9–15,18,19 , spectroscopic investigations 29,30,32,34,36,43,44 , and molecular dynamic simulations of AMPA and NMDA receptors 8,45,46 show that the protein occupies multiple conformations under any given condition and such diversity in conformation is consistent with the diversity of states as seen in single channel recordings of these receptors. More importantly, these studies suggest that the receptor function is dictated to a large extent by conformational selection.…”

Section: Discussionsupporting

confidence: 63%

The structural arrangement at intersubunit interfaces in homomeric kainate receptors

Litwin

Carrillo

Shaikh

et al. 2019

Sci Rep

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Kainate receptors are glutamate-gated cation-selective channels involved in excitatory synaptic signaling and are known to be modulated by ions. Prior functional and structural studies suggest that the dimer interface at the agonist-binding domain plays a key role in activation, desensitization, and ion modulation in kainate receptors. Here we have used fluorescence-based methods to investigate the changes and conformational heterogeneity at these interfaces associated with the resting, antagonist-bound, active, desensitized, and ion-modulated states of the receptor. These studies show that in the presence of Na + ions the interfaces exist primarily in the coupled state in the apo, antagonist-bound and activated (open channel) states. Under desensitizing conditions, the largely decoupled dimer interface at the agonist-binding domain as seen in the cryo-EM structure is one of the states observed. However, in addition to this state there are several additional states with lower levels of decoupling. Replacing Na + with Cs + does not alter the FRET efficiencies of the states significantly, but shifts the population to the more decoupled states in both resting and desensitized states, which can be correlated with the lower activation seen in the presence of Cs + .

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Section: Discussionsupporting

confidence: 63%

The structural arrangement at intersubunit interfaces in homomeric kainate receptors

Litwin

Carrillo

Shaikh

et al. 2019

Sci Rep

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show abstract

“…To investigate this intriguing possibility further, we next dissected this initial large-scale conformational step in greater detail (Figure 8, step 1). Gating is triggered by ligand binding, which induces clamshell closure (Mayer, 2005; Oswald, 2007). The closed conformation is stabilized by hydrogen bonds across the cleft, such as the E402–T686 pair, the side chains of which approach within 2.7 Å on cleft closure (Figure 7A; Armstrong and Gouaux, 2000).…”

Section: Resultsmentioning

confidence: 99%

Gating motions underlie AMPA receptor secretion from the endoplasmic reticulum

Penn

Williams

Greger

2008

EMBO J

105

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Ion channel biogenesis involves an intricate interplay between subunit folding and assembly. Channel stoichiometries vary and give rise to diverse functions, which impacts on neuronal signalling. AMPA glutamate receptor (AMPAR) assembly is modulated by RNA processing. Here, we provide mechanistic insight into this process. First, we show that a single alternatively spliced residue within the ligand-binding domain alters AMPAR secretion from the ER. Local contacts differ between Leu758 of the GluR2-flop splice form as compared with the flip-specific Val758, which is transmitted globally to alter resensitization kinetics. Detailed biochemical and functional analysis of mutants suggest that AMPARs sample the gating cascade prior to ER export. Irreversibly locking the receptor within various states of the cascade severely attenuates ER transit. Alternative RNA processing by contrast, shifts equilibria between transition states reversibly and thereby modulates secretion kinetics. These data reveal how RNA processing tunes AMPAR biogenesis, and imply that gating transitions in the ER determine iGluR secretory traffic.

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“…3,4 The C-terminal domain is involved in receptor localization. 5 In contrast, the function of the NTD is not established.…”

Section: Introductionmentioning

confidence: 99%

Intrinsic Motions in the N-Terminal Domain of an Ionotropic Glutamate Receptor Detected by Fluorescence Correlation Spectroscopy

Jensen

Sukumaran

Johnson

et al. 2011

Journal of Molecular Biology

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Flexibility of a Glutamate-Binding Domain

Cited by 4 publications

References 13 publications

The structural arrangement at intersubunit interfaces in homomeric kainate receptors

The structural arrangement at intersubunit interfaces in homomeric kainate receptors

Gating motions underlie AMPA receptor secretion from the endoplasmic reticulum

Intrinsic Motions in the N-Terminal Domain of an Ionotropic Glutamate Receptor Detected by Fluorescence Correlation Spectroscopy

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