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Kainate receptor modulation by NETO2

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Abstract

Glutamate-gated kainate receptors are ubiquitous in the central nervous system of vertebrates, mediate synaptic transmission at the postsynapse and modulate transmitter release at the presynapse1,2,3,4,5,6,7. In the brain, the trafficking, gating kinetics and pharmacology of kainate receptors are tightly regulated by neuropilin and tolloid-like (NETO) proteins8,9,10,11. Here we report cryo-electron microscopy structures of homotetrameric GluK2 in complex with NETO2 at inhibited and desensitized states, illustrating variable stoichiometry of GluK2–NETO2 complexes, with one or two NETO2 subunits associating with GluK2. We find that NETO2 accesses only two broad faces of kainate receptors, intermolecularly crosslinking the lower lobe of ATDA/C, the upper lobe of LBDB/D and the lower lobe of LBDA/C, illustrating how NETO2 regulates receptor-gating kinetics. The transmembrane helix of NETO2 is positioned proximal to the selectivity filter and competes with the amphiphilic H1 helix after M4 for interaction with an intracellular cap domain formed by the M1–M2 linkers of the receptor, revealing how rectification is regulated by NETO2.

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Fig. 1: Architectures of the GluK2–NETO2 complexes.
Fig. 2: Extracellular interactions between GluK2 and NETO2.
Fig. 3: Ion conduction pore of GluK2 and the modulation mechanism of inward rectification.
Fig. 4: Architecture of the desensitized GluK2–NETO2 complex.

Data availability

The 3D cryo-EM density maps of the antagonist DNQX-bound GluK2-1×NETO2, LBD–TMD of the GluK2-1×NETO2, GluK2-2×NETO2, GluK2-1×NETO2asymLBD complex and the agonist kainate-bound desensitized GluK2-1×NETO2des complex have been deposited in the Electron Microscopy Database under the accession codes EMD-31462, EMD-31464, EMD-31463, EMD-31459 and EMD-31460, respectively. The cryo-EM map of LBD–TMD of the GluK2-2×NETO2 complexes have been deposited as an additional map under entry EMD-31463. The coordinates for the structures have been deposited in the PDB under accession codes 7F59, 7F5B, 7F5A, 7F56 and 7F57, respectively. Source data are provided with this paper.

Change history

  • 27 September 2021

    The linking to some of the Supplementary Information files was originally incorrect and has now been amended.

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Acknowledgements

We thank X. Huang, B. Zhu, X. Li, L. Chen and other staff members at the Center for Biological Imaging (CBI), Core Facilities for Protein Science at the Institute of Biophysics, Chinese Academy of Science (IBP, CAS) for the support in cryo-EM data collection; N. Sheng for providing the cDNAs of GluK2 and NETO2; and Y. Wu for his research assistant service. This work is funded by the Chinese Academy of Sciences Strategic Priority Research Program (grant XDB37030304 to Y.Z. and grant XDB37030301 to X.C.Z.), the National Key R & D Program of China (2019YFA0801603 to Y.S.S.), the National Natural Science Foundation of China (91849112 to Y.S.S. and 31971134 to X.C.Z.), the Natural Science Foundation of Jiangsu Province (BE2019707 to Y.S.S.) and the Fundamental Research Funds for the Central Universities (0903-14380029 to Y.S.S.).

Author information

Authors and Affiliations

Authors

Contributions

Y.Z. conceived the project and supervised the research. L.H., J.S., W.A. and B.Y. carried out molecular cloning and the cell biology experiments. L.H. expressed and purified the protein complex sample. L.H., Y.D. and Y.W. prepared the sample for the cryo-EM study. Y. Gao. L.H., Y.W. and Y.D. carried out cryo-EM data collection. Y. Gao and Y.Z. processed the cryo-EM data and prepared the figures. B.L. and H.L. built and refined the atomic model. Y.Z. and X.C.Z. analysed the structure. Y.Z. and Y.S.S. designed the electrophysiological study. J.S. and Y. Ge performed the electrophysiological analysis. Y.Z. prepared the initial draft of the manuscript. X.C.Z., Y.S.S. and Y.Z. edited the manuscript with input from all authors in the final version.

Corresponding authors

Correspondence to Xuejun Cai Zhang, Yun Stone Shi or Yan Zhao.

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Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature thanks Ingo Greger and Geoffrey Swanson for their contribution to the peer review of this work. Peer reviewer reports are available.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data figures and tables

Extended Data Fig. 1 Functional study and purification of GluK2-Neto2 complex.

a, b, Outside-out recording of the WT GluK2 and GluK2F107L, in the absence or presence of Neto2. c, Statistical analysis of the desensitization time constant of the WT GluK2 and GluK2F107L, with or without Neto2 (GluK2, n = 12, GluK2 + Neto2, n = 14; GluK2F107L, n = 10; GluK2F107L + Neto2, n = 10). Each symbol represents a single cell recording, and n value represents biologically independent cells for statistical analysis. Significances were determined using two-sided unpaired t-test. ****, P < 0.0001. Similar results were reproduced from two independent experiments. Error bars stand for S.E.M. d, Fluorescence-detection size-exclusion chromatography (FSEC) analysis of the co-expressed GluK2-mCherry (red) and Neto2-GFP (green). The experiments were repeated independently with more than three times with similar results. e, Size-exclusion chromatography (SEC) profile of the purified GluK2-Neto2 complex. Fractions within the dashed lines were pooled for cryo-EM sample preparation. The experiments were repeated independently with more than three times with similar results. (f) Coomassie blue-stained SDS-PAGE gel of the pooled fractions. The gel was repeated three times from different batches of purification with similar results. The uncropped gel can be found in Supplementary Fig. 1.

Source data

Extended Data Fig. 2 Cryo-EM data analysis of GluK2-1×Neto2, GluK2-2×Neto2, and GluK2-1×Neto2asymLBD complex.

a, Flowchart of cryo-EM data processing. A total of 5,448 movie stacks were collected and motion-corrected, followed by CTF estimation and particle picking. A representative motion-corrected micrograph of this dataset is shown here (Scale bar = 40 nm). The experiments were repeated three times with similar results. Particles were cleaned and classified using several rounds of 2D and 3D classifications, which generated 3 classes, representing GluK2-1×Neto2, GluK2-2×Neto2, and GluK2-1×Neto2asymLBD, respectively. Particles were then submitted to further 3D classifications separately to improve resolutions. Focused classification and refinement of LBD-TMD were conducted on the particles of GluK2-1×Neto2 complex. Masks used in focused processing were overlaid on GluK2 map (green) as transparent grey surfaces alongside the arrows. b, e, h, k, Angular distribution of the particles contributing the final reconstruction for GluK2-1×Neto2asymLBD complex (b), GluK2-2×Neto2 complex (e), GluK2-1×Neto2 complex (h), and LBD-TMD (k). The length of each spike indicates of the number of particles in the designated orientation. c, f, i, l, Sharpened map of GluK2-1×Neto2asymLBD complex (c), GluK2-2×Neto2 complex (f), GluK2-1×Neto2 complex (i), and LBD-TMD (l), colored according to local resolution estimation. d, g, j, m, The half-map (red) and model-map (black) Fourier shell correlation (FSC) of GluK2-1×Neto2asymLBD complex (d), GluK2-2×Neto2 complex (g), GluK2-1×Neto2 complex (j), and LBD-TMD (m).

Source data

Extended Data Fig. 3 EM maps for transmembrane helices and the LBD-TMD.

a, Transmembrane helices M1−M4, and the M1-M2 loop. EM maps are shown as transparent grey surfaces. Some sidechains are shown as sticks. b, EM maps for LBD and TMD layers. CUB2 and LDLa of Neto2 are colored in orange. Receptor is colored in purple. N-glycans and a lipid tail are shown in sticks.

Extended Data Fig. 4 Structural comparison of ATD and LBD layers.

a, Superimposition of antagonist bound LBDs of 5KUH (grey) and GluK2-1×Neto2 (red). b, Comparison of the ATDA-LBDB and ATDC-LBDD segments between subunit A (grey) and C (blue) of the GluK2-1×Neto2, GluK2-2×Neto2 and GluK2-1×Neto2asymLBD complexes, using LBD as a reference. The COMs of the ATD R1/R2-lobe of subunits A and C are depicted as rectangles or triangles, respectively. The COMs of the LBD layer is marked as a circle. c, Superimposition of ATD-CUB1 interactions between GluK2-1×Neto2asymLBD (grey) and GluK2-1×Neto2 (red, orange and blue).

Extended Data Fig. 5 Sequence alignments and structural comparison of the KARs.

ad, Sequence alignments of the GluK members in Rat norvegicus, numbered according to full-length subunits. Secondary structures of GluK2 are marked above the sequence alignment. Dashes represent gaps. Conserved residues are shaded in grey. Residues which are involved in Neto2 interaction are indicated by triangle symbol. e, Structural comparison of the LBD of GluK2 with GluK1 (3FUZ, green), GluK3 (3U92, cyan), GluK4 (5IKB, magenta), and GluK5 (7KS0, yellow), respectively. D1- and D2- lobes and Loop 1 are indicated.

Extended Data Fig. 6 Representative desensitization and rectification traces.

a, Representative desensitization traces of GluK2 and mutants responded to 60 ms application of 10 mM glutamate were normalized and aligned to the peak. Superimposed responses of the receptor alone and the receptor-Neto2 complex were shown in black and green traces, respectively. b, Normalized current-voltage relationship of GluK2 mutants in the absence and presence of Neto2. n value represents independent cells for analysis. c, Representative desensitization traces and related statistical analysis (GluA2, n = 16; GluA2K2ICD, n = 12). Each symbol represents a single cell recording, and n value represents biologically independent cells for statistical analysis. Significances were determined using two-sided unpaired t-test. Not significant (ns), P = 0.0755. No adjustments were made for multiple comparisons. Error bars stand for S.E.M. The H1-helix is composed of residues 857FCSAMVEELRMSLK870 and removed in GluK2ΔH1 construct. The amino acid sequence of the ICD of GluK2 and GluA2 between M1-M2 helices are 587YEWYNPHPCNPDSDVVEN604 and 570YEWHTEEFEDGRETQSSESTNE591, respectively, which are involved in the ICD swapping constructs of GluA2K2ICD and GluK2A2ICD. d, I-V relationship for GluA2, GluK2 and related mutants. Desensitization curves (10 mM glutamate for 200 ms) were recorded at holding potential ranging from −100 to +100 mV in 20 mV increasement. Traces were normalized to the peak value at −100 mV.

Source data

Extended Data Fig. 7 Interactions stabilizing the pore helix M2.

a, EM density map of the LBD and TMD layers of the GluK2-1×Neto2 complex. Subunits A/C and B/D of GluK2 are colored in blue and red, respectively. The Neto2 protein is colored in orange. N-glycans are colored in yellow. b, The ion conduction pore and its profile of the GluK2-Neto2 complex. Pore loops are colored in green. A cation ion is shown as a grey sphere, overlaid with corresponding EM density colored in marine. Q621, T652, A656, and T660 are shown in sticks. Constriction sites are indicated in the pore profile. c, The TM helices of the GluK2 (red and blue) and the Neto2 (yellow) are shown as cartoon. The EM density of M2 helix are shown as transparent grey surface. Critical residues involved in interactions are shown as sticks. d, “Top-down” view of M2 helices and the pore loops. Q621 residues are shown in sticks.

Extended Data Fig. 8 Cryo-EM data analysis of GluK2-1×Neto2des complex.

a, Flowchart of cryo-EM data processing. A total of 2,957 movie stacks were collected and motion-corrected, followed by CTF estimation and particle picking. A representative motion-corrected micrograph of this dataset is shown here (Scale bar = 40 nm). The experiments were repeated three times with similar results. Three-dimensional classification generated 8 classes, 4 of which displayed classical structures of kainate receptors. Another round of 3D classification was then performed, followed by Ab-initio Reconstruction and Heterologous Refinement to furtherly improve the quality of map. b, Angular distribution of the particles contributing the final reconstruction of GluK2-1×Neto2des complex. The length of each spike indicates of the number of particles in the designated orientation. c, Sharpened map of GluK2-1×Neto2des complex, colored according to local resolution estimation. d, The half-map (red) and model-map (black) Fourier shell correlation.

Source data

Extended Data Fig. 9 Conformational change of GluK2-Neto2 complex upon desensitization.

a, Superimposition of agonist bound LBDs of 4BDM (grey) and GluK2-1×Neto2des (red). b, Superimposition of ATD-CUB1-LBD interactions between GluK2-1×Neto2asymLBD (grey) and GluK2-1×Neto2des (red, orange and blue). c, Organization of the D1 lobe of the GluK2-1×Neto2des (red and blue) and desensitized GluK2 alone (grey). COMs of the lobes are depicted as black dots. Distances and angles are indicated. d, The LBD rearrangement between GluK2-1×Neto2 and GluK2-1×Neto2des upon desensitization. e, Displacement of LBD at B-position of GluK2-1×Neto2des complex (red, blue and orange) compared with desensitized GluK2 (5KUF, grey).

Extended Data Table 1 Cryo-EM data collection, refinement and validation statistics

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He, L., Sun, J., Gao, Y. et al. Kainate receptor modulation by NETO2. Nature 599, 325–329 (2021). https://doi.org/10.1038/s41586-021-03936-y

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