Abstract
Uncoupling protein 1 (UCP1) conducts protons through the inner mitochondrial membrane to uncouple mitochondrial respiration from ATP production, thereby converting the electrochemical gradient of protons into heat1,2. The activity of UCP1 is activated by endogenous fatty acids and synthetic small molecules, such as 2,4-dinitrophenol (DNP), and is inhibited by purine nucleotides, such as ATP3,4,5. However, the mechanism by which UCP1 binds to these ligands remains unknown. Here we present the structures of human UCP1 in the nucleotide-free state, the DNP-bound state and the ATP-bound state. The structures show that the central cavity of UCP1 is open to the cytosolic side. DNP binds inside the cavity, making contact with transmembrane helix 2 (TM2) and TM6. ATP binds in the same cavity and induces conformational changes in TM2, together with the inward bending of TM1, TM4, TM5 and TM6 of UCP1, resulting in a more compact structure of UCP1. The binding site of ATP overlaps with that of DNP, suggesting that ATP competitively blocks the functional engagement of DNP, resulting in the inhibition of the proton-conducting activity of UCP1.
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Data availability
Cryo-EM maps of UCP1–12F2 sybody in the nucleotide-free state, the DNP-bound state and the ATP-bound state have been deposited in the Electron Microscopy Data Bank under the ID codes: EMD-34644, EMD-35928 and EMD-34645, respectively. Atomic models of UCP1–12F2 sybody in the nucleotide-free state, the DNP-bound state and the ATP-bound state have been deposited in the Protein Data Bank under the ID codes: 8HBV, 8J1N, and 8HBW, respectively. The entries 2C3E, 1OKC and 7RXC used in this study were downloaded from the Protein Data Bank. The simulated structure of DNP-bound AAC1 was downloaded from Zenodo (https://doi.org/10.5281/zenodo.5058463). Source data are provided with this paper.
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Acknowledgements
We thank Y. Qiu and K. Xue for their helpful discussions, M. Seeger for providing the sybody library, and D. Li and T. Li for technical advice on sybody screening. Cryo-EM data collection was supported by the Electron microscopy laboratory and the Cryo-EM platform of Peking University with the assistance of X. Li, C. Qin, X. Pei, X. Hui, Z. Guo and G. Wang. Part of the structural computation was also performed on the Computing Platform of the Center for Life Science and High-performance Computing Platform of Peking University. We thank the National Center for Protein Sciences at Peking University in Beijing, China for assistance with the negative-stain EM. The work is supported by grants from the Ministry of Science and Technology of China (National Key R&D Program of China, 2022YFA0806504 to L.C.), the National Natural Science Foundation of China (91957201, 32225027 and 31821091 to L.C. and 8200907150 to Y.K.) and the Center For Life Sciences (to L.C.). Y.K. is supported by the Boya Postdoctoral Fellowship of Peking University.
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L.C. initiated the project and wrote the draft of the manuscript. Y.K. carried out experiments with the help of L.C. Both authors contributed to preparation of the manuscript.
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Extended data figures and tables
Extended Data Fig. 1 Biochemistry characterization of UCP1-12F2-legobody in nanodisc.
a, Amino acid sequence of 12F2 sybody. Complementarity-determining regions (CDR1-3) are indicated. Variable amino acids in the sybody library are highlighted in red. b, Schematic diagram of the assembled UCP1-12F2-legobody. c, Proton influx rate of the proteoliposome reconstituted with UCP1, the same amount of UCP1-12F2-legobody, or without UCP1 (empty liposome). Data are shown as mean ± standard deviations, n = 3 technical replicates. The experiment has been independently repeated twice with similar results. Data for the UCP1-12F2-legobody proteoliposome is the same as that shown in Fig. 1c. d, Sliver stained SDS-PAGE of detergent-solubilized liposomes from c. The bands corresponding to MBP-PrA/G, Fab_8D3_2, ALFA-strep-UCP1, and 12F2 sybody were indicated. The experiments were repeated independently twice with similar results. For gel source data, see Supplementary Fig. 1. e, ATP-dependent thermal stabilization of UCP1 (pH 6.0) in the presence or absence of 12F2 sybody when heating at 49 °C. Data are shown as mean ± standard deviations, n = 3 biologically independent samples. f, Size-exclusion chromatography of the UCP1-12F2-legobody nanodisc on a Superose 6 increase column. The fractions between the red vertical lines were pooled and concentrated for cryo-EM sample preparation. g, Coomassie brilliant blue staining of SDS-PAGE of fractions from size-exclusion chromatography in f. The bands corresponding to MBP-PrA/G, Fab_8D3_2, ALFA-strep-UCP1, MSP NW9, and 12F2 sybody were indicated. The fractions indicated by the red line were used for cryo-EM sample preparation. The experiments were repeated independently twice with similar results. For gel source data, see Supplementary Fig. 1.
Extended Data Fig. 2 Cryo-EM image analysis of UCP1 in the nucleotide-free state.
a, Representative raw micrograph (5,592 in total) of UCP1-12F2-legobody in the nucleotide-free state. Scale bar, 100 nm. b, 2D-class averages of UCP1-12F2-legobody in the nucleotide-free state. Scale bar, 150 Å. c, Cryo-EM data processing workflow of UCP1-12F2-legobody in the nucleotide-free state. For details, see ‘Cryo-EM image analysis’ in the Methods section. d, Gold-standard Fourier Shell Correlation (FSC) of the local-refined map shown in c after correction of masking effects. e, Angular distribution of the final reconstruction. f, A cut-open view of the local resolution map of the UCP1-12F2 sybody region in the nucleotide-free state. Scale bar, 2.5–3.7 Å.
Extended Data Fig. 3 Cryo-EM image analysis of UCP1 in the DNP-bound state.
a, Representative raw micrograph (13,917 in total) of UCP1-12F2-legobody in the DNP-bound state. Scale bar, 100 nm. b, 2D-class averages of UCP1-12F2-legobody in the DNP-bound state. Scale bar, 150 Å. c, Cryo-EM data processing workflow of UCP1-12F2-legobody in the DNP-bound state. For details, see ‘Cryo-EM image analysis’ in the Methods section. d, Gold-standard Fourier Shell Correlation (FSC) of the local-refined map shown in c after correction of masking effects. e, Angular distribution of the final reconstruction. f, A cut-open view of the local resolution map of the UCP1-12F2 sybody region in the DNP-bound state. The density corresponding to DNP is indicated by an arrow. Scale bar, 2.5–3.7 Å.
Extended Data Fig. 4 Cryo-EM image analysis of UCP1 in the ATP-bound state.
a, Representative raw micrograph (6,765 in total) of UCP1-12F2-legobody in the ATP-bound state. Scale bar, 100 nm. b, 2D-class averages of UCP1-12F2-legobody in the ATP-bound state. Scale bar, 150 Å. c, Cryo-EM data processing workflow of UCP1-12F2-legobody in the ATP-bound state. For details, see ‘Cryo-EM image analysis’ in the Methods section. d, Gold-standard Fourier Shell Correlation (FSC) of the local-refined map shown in c after correction of masking effects. e, Angular distribution of the final reconstruction. f, A cut-open view of the local resolution map of the UCP1-12F2 sybody region in the ATP-bound state. The density corresponding to ATP is indicated by an arrow. Scale bar, 2.5–3.7 Å.
Extended Data Fig. 5 Representative electron density maps.
a, Electron density maps of helices in the nucleotide-free state are shown in blue meshes. b, Electron density maps of helices in the DNP-bound state are shown in blue meshes. c, Electron density maps of helices in the ATP-bound state are shown in blue meshes. The contour level in a-c was 6 σ. d, Cartoon representation of UCP1 in complex with 12F2 sybody in the nucleotide-free state. UCP1 was colored the same as in Fig. 1g, 12F2 sybody was colored in gray, CDR1, CDR2, and CDR3 of 12F2 sybody were colored in cyan, pink, and orange, respectively. e, Close-up view of the interacting region between UCP1 and 12F2 sybody boxed in d. Key interacting residues are shown as sticks. Hydrogen bonds are indicated by dashed lines. f, Electron density map of cardiolipin in the nucleotide-free state is shown in blue meshes, contoured at 6 σ. g, Electron density map of DNP in the DNP-bound state is shown in blue meshes, contoured at 5 σ. h, Electron density map of ATP in the ATP-bound state is shown in blue meshes, contoured at 6 σ.
Extended Data Fig. 6 Sequence alignment of UCP1 with other related SLC25 family proteins.
The sequence alignment of human UCP1 (HsUCP1), mouse UCP1 (MmUCP1), human UCP2 (HsUCP2), human UCP3 (HsUCP3), thermophilus AAC (TtAac), and bovine AAC1 (BtAAC1). Highly conserved residues are shaded in red. Relatively conserved residues are colored in red. Secondary structures are shown above with the same color as in Fig. 1g. Residues for binding with the triphosphate group and adenosine group of ATP are denoted by * or ○, respectively. Residues for binding with DNP are denoted by ×. ATP-binding residues in TtAac proposed by ref. 24. are denoted by +.
Extended Data Fig. 7 Structural comparison of UCP1 with AAC1.
a, Structural comparison of UCP1 in the nucleotide-free state (colored, same as in Fig. 1g) and CATR-bound AAC1 (gray, PDB ID: 2C3E)26. CDL are shown as sticks (orange in UCP1 and gray in AAC1). b, A 120° rotated side view of a. PC in UCP1 is shown as orange sticks, and CDL in AAC1 is shown as gray sticks. c, A 120° rotated side view of b. PC in UCP1 is shown as orange sticks, and CDL in AAC1 is shown as gray sticks. d, Structural comparison of UCP1 in the nucleotide-free state (colored, same as in Fig. 1g) and CATR-bound AAC1 (gray, PDB ID: 1OKC)25. Helices are shown as cylinders. CATR is shown as spheres. e, A 90° rotated top view of d. f, A 180° rotated bottom view of e. g, Structural comparison of UCP1 in the DNP-bound state (colored, same as in Fig. 1g) and the nucleotide-free state (gray). Helices are shown as cylinders. DNP is shown as cyan spheres. h, A 90° rotated top view of g. i, DNP-dependent decrease of thermostability of WT UCP1 and mutants (pH 7.4) at 35 °C (mean ± standard deviations, n = 3 biologically independent samples). j, Structural comparison of UCP1 in the ATP-bound state (colored, same as in Fig. 1g) and CATR-bound AAC1 (gray, PDB ID: 1OKC)25. Helices are shown as cylinders. ATP is shown as pink spheres, and CATR is shown as gray spheres. k, A 90° rotated top view of j. l, Structural comparison of UCP1 in the DNP-bound state (colored, same as in Fig. 1g) and DNP-bound AAC1 (c-state, gray, simulated structure)4. Helices are shown as cylinders. DNP is shown as spheres. m, A 90° rotated top view of l.
Extended Data Fig. 8 Nucleoside triphosphate binding site in UCP1.
a, Cartoon representation of UCP1 in the ATP-bound state (colored, same as in Fig. 1g). ATP is shown as gray sticks. b, Close-up view of the ATP-binding site boxed in a. The side chain of N187 is shown as sticks, and the hydrogen bond is indicated by a dashed line. c-e, The binding poses of GTP (c), CTP (d), and UTP (e) were modeled according to the structure of UCP1 in the ATP-bound state. The side chain of N187 is shown as sticks, and the hydrogen bond is indicated by a dashed line. f-l, Melting curves of wild-type UCP1 (f) and UCP1 mutants (pH 6.0), including R83A (g), Q84A (h), R91A (i), R182A (j), I186A (k), and E190A (l), in the presence or absence of 1 mM ATP. Melting temperatures (Tm) are indicated. Data are shown as mean ± standard deviations, n = 3 biologically independent samples.
Extended Data Fig. 9 Hypothetic working model of UCP1.
a, Hypothetic working models of UCP1 in the nucleotide-free state, DNP-bound state and ATP-bound state. The DNP-bound conductive state is not captured and outlined by dashed lines. b-d, Chemical structures of OA (b), DNP (c), and FCCP (d).
Supplementary information
Supplementary Figure 1
Uncropped SDS-PAGE gels. Cropped regions shown in Extended Data Fig. 1d, g are indicated with dashed lines.
Supplementary Video 1
Conformational changes of UCP1 upon DNP binding. The morphing of UCP1 between the nucleotide-free state and the DNP-bound state.
Supplementary Video 2
Conformational changes of UCP1 upon ATP binding. The morphing of UCP1 between the nucleotide-free state and the ATP-bound state.
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Kang, Y., Chen, L. Structural basis for the binding of DNP and purine nucleotides onto UCP1. Nature 620, 226–231 (2023). https://doi.org/10.1038/s41586-023-06332-w
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DOI: https://doi.org/10.1038/s41586-023-06332-w
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