scholarly journals Architecture and structural dynamics of the heteromeric GluK2/K5 kainate receptor

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Nandish Khanra ◽  
Patricia MGE Brown ◽  
Amanda M Perozzo ◽  
Derek Bowie ◽  
Joel Meyerson
Keyword(s):  
Ligand Binding ◽  
Structural Dynamics ◽  
Kainate Receptors ◽  
Kainate Receptor ◽  
Assembly Rules ◽  
Structural Rearrangements ◽  
Closed Channel ◽  
Binding Domains ◽  
The Brain ◽  
Channel Structures

Kainate receptors (KARs) are L-glutamate-gated ion channels that regulate synaptic transmission and modulate neuronal circuits. KARs have strict assembly rules and primarily function as heteromeric receptors in the brain. A longstanding question is how KAR heteromer subunits organize and coordinate together to fulfill their signature physiological roles. Here we report structures of the GluK2/GluK5 heteromer in apo, antagonist-bound, and desensitized states. The receptor assembles with two copies of each subunit, ligand binding domains arranged as two heterodimers, and GluK5 subunits proximal to the channel. Strikingly, during desensitization GluK2 but not GluK5 subunits undergo major structural rearrangements to facilitate channel closure. We show how the large conformational differences between antagonist-bound and desensitized states are mediated by the linkers connecting the pore helices to the ligand-binding domains. This work presents the first KAR heteromer structure, reveals how its subunits are organized, and resolves how the heteromer can accommodate functionally-distinct closed channel structures.

scholarly journals Structural Insights into GluK3-kainate Receptor Desensitization and Recovery

2019 ◽  
Author(s):  
Jyoti Kumari ◽  
Rajesh Vinnakota ◽  
Janesh Kumar
Keyword(s):  
Structural Changes ◽  
Mutational Analysis ◽  
Receptor Activation ◽  
Kainate Receptors ◽  
Kainate Receptor ◽  
Amino Terminal ◽  
Binding Domains ◽  
Domain Interactions ◽  
Structural Insights

AbstractGluK3-kainate receptors are atypical members of the iGluR family that reside at both the pre- and postsynapse and play key role in regulation of synaptic transmission. For better understanding of structural changes that underlie receptor recovery from desensitized state, GluK3 receptors were trapped in desensitized and resting/closed states and structures analyzed using single particle cryo-electron microscopy. We show that receptor recovery from desensitization requires major rearrangements of the ligand binding domains (LBD) while the amino terminal (ATD) and transmembrane domains remain virtually unaltered. While, the desensitized GluK3 has domain organization as seen earlier for another kainate receptor-GluK2, antagonist bound GluK3 trapped a partially “recovered” state with only two LBD domains in dimeric arrangement necessary for receptor activation. Using these structures as guide, we show that the N-linked glycans at the interface of GluK3 ATD and LBD likely mediate inter-domain interactions and attune receptor-gating properties. Mutational analysis also identifies putative N-glycan interacting residues. These results provide a molecular framework for understanding gating properties unique to GluK3 and identify role of N-linked glycosylation in their modulation.

Structural dynamics of the GluK3-kainate receptor neurotransmitter binding domains revealed by cryo-EM

2020 ◽  
Vol 149 ◽  
pp. 1051-1058 ◽  
Author(s):  
Jyoti Kumari ◽  
Ameya D. Bendre ◽  
Sumedha Bhosale ◽  
Rajesh Vinnakota ◽  
Ananth P. Burada ◽  
...  
Keyword(s):  
Structural Dynamics ◽  
Kainate Receptor ◽  
Binding Domains

scholarly journals Glycine activated ion channel subunits encoded by ctenophore glutamate receptor genes

2015 ◽  
Vol 112 (44) ◽  
pp. E6048-E6057 ◽  
Author(s):  
Robert Alberstein ◽  
Richard Grey ◽  
Austin Zimmet ◽  
David K. Simmons ◽  
Mark L. Mayer
Keyword(s):  
Ligand Binding ◽  
Salt Bridge ◽  
Binding Pocket ◽  
Kainate Receptors ◽  
Mnemiopsis Leidyi ◽  
Binding Assays ◽  
Sequence Alignments ◽  
Binding Domains ◽  
Binding Cavity ◽  
Future Work

Recent genome projects for ctenophores have revealed the presence of numerous ionotropic glutamate receptors (iGluRs) in Mnemiopsis leidyi and Pleurobrachia bachei, among our earliest metazoan ancestors. Sequence alignments and phylogenetic analysis show that these form a distinct clade from the well-characterized AMPA, kainate, and NMDA iGluR subtypes found in vertebrates. Although annotated as glutamate and kainate receptors, crystal structures of the ML032222a and PbiGluR3 ligand-binding domains (LBDs) reveal endogenous glycine in the binding pocket, whereas ligand-binding assays show that glycine binds with nanomolar affinity; biochemical assays and structural analysis establish that glutamate is occluded from the binding cavity. Further analysis reveals ctenophore-specific features, such as an interdomain Arg-Glu salt bridge, present only in subunits that bind glycine, but also a conserved disulfide in loop 1 of the LBD that is found in all vertebrate NMDA but not AMPA or kainate receptors. We hypothesize that ctenophore iGluRs are related to an early ancestor of NMDA receptors, suggesting a common evolutionary path for ctenophores and bilaterian species, and suggest that future work should consider both glycine and glutamate as candidate neurotransmitters in ctenophore species.

scholarly journals Paired opposing leukocyte receptors recognizing rapidly evolving ligands are subject to homogenization of their ligand binding domains

2011 ◽  
Vol 63 (12) ◽  
pp. 809-820 ◽  
Author(s):  
Sigbjørn Fossum ◽  
Per Christian Saether ◽  
John Torgils Vaage ◽  
Michael Rory Daws ◽  
Erik Dissen
Keyword(s):  
Ligand Binding ◽  
Binding Domains ◽  
Leukocyte Receptors

scholarly journals Structure And Stability Of Ligand Binding Core Dimer Assembly Controls Desensitization In A Kainate Receptor

2009 ◽  
Vol 96 (3) ◽  
pp. 491a
Author(s):  
Charu Chaudhry ◽  
Matthew C. Weston ◽  
Peter Schuck ◽  
Christian Rosenmund ◽  
Mark L. Mayer
Keyword(s):  
Ligand Binding ◽  
Kainate Receptor ◽  
Structure And Stability ◽  
Binding Core

scholarly journals Biochemical and NMR Mapping of the Interface between CREB-binding Protein and Ligand Binding Domains of Nuclear Receptor

2004 ◽  
Vol 280 (7) ◽  
pp. 5682-5692 ◽  
Author(s):  
Fabrice A. C. Klein ◽  
R. Andrew Atkinson ◽  
Noelle Potier ◽  
Dino Moras ◽  
Jean Cavarelli
Keyword(s):  
Ligand Binding ◽  
Nuclear Receptor ◽  
Binding Protein ◽  
Creb Binding Protein ◽  
Binding Domains

Ligand modulates the conversion of DNA-bound vitamin D3 receptor (VDR) homodimers into VDR-retinoid X receptor heterodimers

1994 ◽  
Vol 14 (5) ◽  
pp. 3329-3338
Author(s):  
B Cheskis ◽  
L P Freedman
Keyword(s):  
Ligand Binding ◽  
Vitamin D3 ◽  
Hormone Receptors ◽  
Steroid Receptors ◽  
Dependent Manner ◽  
D3 Receptor ◽  
Vitamin D3 Receptor ◽  
Binding Domains

Protein dimerization facilitates cooperative, high-affinity interactions with DNA. Nuclear hormone receptors, for example, bind either as homodimers or as heterodimers with retinoid X receptors (RXR) to half-site repeats that are stabilized by protein-protein interactions mediated by residues within both the DNA- and ligand-binding domains. In vivo, ligand binding among the subfamily of steroid receptors unmasks the nuclear localization and DNA-binding domains from a complex with auxiliary factors such as the heat shock proteins. However, the role of ligand is less clear among nuclear receptors, since they are constitutively localized to the nucleus and are presumably associated with DNA in the absence of ligand. In this study, we have begun to explore the role of the ligand in vitamin D3 receptor (VDR) function by examining its effect on receptor homodimer and heterodimer formation. Our results demonstrate that VDR is a monomer in solution; VDR binding to a specific DNA element leads to the formation of a homodimeric complex through a monomeric intermediate. We find that 1,25-dihydroxyvitamin D3, the ligand for VDR, decreases the amount of the DNA-bound VDR homodimer complex. It does so by significantly decreasing the rate of conversion of DNA-bound monomer to homodimer and at the same time enhancing the dissociation of the dimeric complex. This effectively stabilizes the bound monomeric species, which in turn serves to favor the formation of a VDR-RXR heterodimer. The ligand for RXR, 9-cis retinoic acid, has the opposite effect of destabilizing the heterodimeric-DNA complex. These results may explain how a nuclear receptor can bind DNA constitutively but still act to regulate transcription in a fully hormone-dependent manner.

Sign in / Sign up

Export Citation Format

Share Document