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Conformational and functional changes of the native neuropeptide somatostatin occur in the presence of copper and amyloid-β

Abstract

The progression of neurodegenerative disorders can lead to impaired neurotransmission; however, the role of pathogenic factors associated with these diseases and their impact on the structures and functions of neurotransmitters have not been clearly established. Here we report the discovery that conformational and functional changes of a native neuropeptide, somatostatin (SST), occur in the presence of copper ions, metal-free amyloid-β (Aβ) and metal-bound Aβ (metal–Aβ) found as pathological factors in the brains of patients with Alzheimer’s disease. These pathological elements induce the self-assembly of SST and, consequently, prevent it from binding to the receptor. In the reverse direction, SST notably modifies the aggregation profiles of Aβ species in the presence of metal ions, attenuating their cytotoxicity and interactions with cell membranes. Our work demonstrates a loss of normal function of SST as a neurotransmitter and a gain of its modulative function against metal–Aβ under pathological conditions.

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Fig. 1: Pathogenic factors of AD and SST studied in this work.
Fig. 2: Conformational and functional changes of SST upon incubation with metal ions.
Fig. 3: Cu(II) coordination to SST and proposed mechanisms for the nucleation of Cu(II)(SST).
Fig. 4: Aβ-mediated aggregation of SST in the absence and presence of metal ions.
Fig. 5: Effects of SST on Aβ aggregation with and without metal ions.
Fig. 6: Influence of SST on the cytotoxicity induced by Aβ species in the absence and presence of metal ions.

Data availability

All experimental details and data supporting the findings of this study are available within the paper and its Supplementary Information. The data are also available from the corresponding authors upon reasonable request. Source data are provided with this paper.

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Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (NRF-2017R1A2B3002585 and NRF-2022R1A3B1077319 (M.H.L.); NRF-2021R1A2C3012159 (S.-H.L.); NRF-2018R1C1B6007430 (K.P.)); the Basic Science Research Program through the NRF funded by the Ministry of Education (NRF-2019R1A6A1A10073887) (M.H.L.); the KAIST Advanced Institute for Science-X (KAIX) Challenge (M.H.L.). J.H. thanks the Global Ph.D. fellowship program for support through the NRF funded by the Ministry of Education (NRF-2019H1A2A1073754).

Author information

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Authors

Contributions

J.H. and M.H.L. designed the research. J.H. performed the spectroscopic measurements (absorbance, fluorescence and CD), PAGE, ESI–MS, docking studies, biochemical assays, TEM and cell studies with data analysis. T.Q. and Y.L. developed the GRABSST sensor. J.Y. and S.-H.L. designed the GRABSST imaging experiment and analysed the data. J.S. and K.P. collected and analysed the spectroscopic data and DFT calculation. E.N. contributed to the immunocytochemistry studies. J.H., E.N., K.P., S.-H.L. and M.H.L. wrote the manuscript with input from all authors.

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Correspondence to Kiyoung Park, Seung-Hee Lee or Mi Hee Lim.

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Nature Chemistry thanks Ujendra Kumar and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Receptor-binding studies of SST treated with and without metal ions.

a, Titration experiments to determine the EC50 value of the GRABSST sensor against SST. Various concentrations of SST were sequentially added to the GRABSST sensor-expressing HEK293T cells at a 1 min interval. The ΔF/F0 values were plotted as a function of log[SST] and fitted to obtain the EC50 value. Data are presented as mean ± s.e.m. (standard error of the mean); n = 9. Conditions: [SST] = 0.003, 0.01, 0.03, 0.05, 0.1, 0.3, 0.5, 1, 3, and 7 μM; 20 mM HEPES, pH 7.4, 150 mM NaCl. b, Change in the fluorescence intensity of the GRABSST sensor upon addition of SST incubated with or without metal ions. Data are presented as mean ± s.e.m. (standard error of the mean); n = 20 (without metal ions), n = 10 (with metal ions). c, Fluorescence measurements of the GRABSST sensor after administration of metal ions and vehicle (buffered solution). Data are presented as mean ± s.e.m. (standard error of the mean); n = 4–10 per group. Conditions: [SST] = 0.5 μM; [MCl2] = 0.5 μM; 20 mM HEPES, pH 7.4, 150 mM NaCl; 24 h incubation; constant agitation. The vertical lines indicate time points when the ΔF/F0 values were quantitatively analyzed and compared between groups.

Source data

Extended Data Fig. 2 DFT models of Cu(II)(SST).

a, Energy-minimized geometry of SST. The amino acid residues that can coordinate to Cu(II) are circled. Yellow, gray, blue, red, and white balls indicate S, C, N, O, and H atoms, respectively. H atoms bonded to carbon atoms are omitted for clarity. b, Comparison of the DFT models of Cu(II)(SST). Total 11 models were constructed and their relative potential energies (ΔE in kcal/mol), the TDDFT-calculated Abs band energies (\(\bar v_{max}\) in cm-1), and EPR gz parameters are summarized. The model Ala1Cys14-I exhibits the highest \(\bar v_{max}\) and the smallest gz value that reproduce the experimental results, with a reasonable stability given the DFT energy error (ca. 5 kcal/mol). c, DFT models (Ala1Cys14-II–IV) of Cu(II)(SST). The Cu(II) center is coordinated to the N-terminal primary amine (Ala1) and water molecules that are hydrogen bonded to Cys14. Three different structures obtained with variations in hydrogen bonding are given, with their relative potential energies at the bottom. The truncated Cu(II) sites used for spectroscopic calculations are depicted at the bottom. Compared to the Cu(II)-free SST structure (coloured lines), major configurational changes were observed and highlighted in dashed circles. Orange, yellow, gray, blue, red, and white balls indicate Cu, S, C, N, O, and H atoms, respectively, and H atoms bonded to carbon atoms are omitted for clarity.

Extended Data Fig. 3 Receptor-binding studies of SST incubated with Aβ40.

a, Change in the fluorescence of the GRABSST sensor upon addition of SST treated with Aβ40 in the absence and presence of metal ions. Data are presented as mean ± s.e.m. (standard error of the mean); n = 19–21 per group. b, Fluorescence measurements of the GRABSST sensor after administration of metal-added and metal-free Aβ40 without SST. Data are presented as mean ± s.e.m. (standard error of the mean); n = 10 per group. Conditions: [SST] = 0.5 μM; [MCl2] = 0.5 μM; [Aβ40] = 0.5 μM; 20 mM HEPES, pH 7.4, 150 mM NaCl; 24 h incubation; constant agitation. The vertical lines indicate time points when the ΔF/F0 values were quantitatively analyzed and compared between groups.

Source data

Supplementary information

Supplementary Information

Supplementary Figs. 1–25, Table 1 and unprocessed gel/Western blot data.

Reporting Summary

Supplementary Data 1

Final coordinates and energy from BP86 calculations on geometry-optimized SST (PDB 2MI1)

Supplementary Data 2

Final coordinates and energy from BP86 calculations on geometry-optimized Ala1-I–III

Supplementary Data 3

Final coordinates and energy from BP86 calculations on geometry-optimized Ala1Lys4-I–II

Supplementary Data 4

Final coordinates and energy from BP86 calculations on geometry-optimized Ala1Cys14-I–IV

Supplementary Data 5

Final coordinates and energy from BP86 calculations on geometry-optimized Cys14 and Lys9Cys14

Source data

Source Data Fig. 2

Unprocessed gels for Fig. 2b

Source Data Fig. 2

Statistical source data for Fig. 2c,f

Source Data Fig. 3

Statistical source data for Fig. 3a,b

Source Data Fig. 4

Unprocessed gels for Fig. 4d,e

Source Data Fig. 5

Statistical source data for Fig. 5b

Source Data Fig. 5

Unprocessed gels for Fig. 5c

Source Data Extended Data Fig. 1

Statistical source data for Extended Data Fig. 1

Source Data Extended Data Fig. 3

Statistical source data for Extended Data Fig. 3

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Han, J., Yoon, J., Shin, J. et al. Conformational and functional changes of the native neuropeptide somatostatin occur in the presence of copper and amyloid-β. Nat. Chem. 14, 1021–1030 (2022). https://doi.org/10.1038/s41557-022-00984-3

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