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Structural basis for membrane remodeling by the AP5–SPG11–SPG15 complex

Nature Structural & Molecular Biology volume 32, pages 1334–1346 (2025)Cite this article

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Abstract

The human spastizin (spastic paraplegia 15, SPG15) and spatacsin (spastic paraplegia 11, SPG11) complex is involved in the formation of lysosomes, and mutations in these two proteins are linked with hereditary autosomal-recessive spastic paraplegia. SPG11–SPG15 can cooperate with the fifth adaptor protein complex (AP5) involved in membrane sorting of late endosomes. We employed cryogenic-electron microscopy and in silico predictions to investigate the structural assemblies of the SPG11–SPG15 and AP5–SPG11–SPG15 complexes. The W-shaped SPG11–SPG15 intertwined in a head-to-head fashion, and the N-terminal region of SPG11 is required for AP5 complex interaction and assembly. The AP5 complex is in a super-open conformation. Our findings reveal that the AP5–SPG11–SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro. These studies provide insights into the structure and function of the spastic paraplegia AP5–SPG11–SPG15 complex, which is essential for the initiation of autolysosome tubulation.

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Fig. 1: Architecture and dynamics of the human SPG11–SPG15 complex.
Fig. 2: Cryo-EM structure of the AP5βtrunk–SPG11–SPG15 complex.
Fig. 3: Interface between the SPG11WD40-hairpin, AP5β5 and AP5ζ.
Fig. 4: Disruption of the SPG11–AP5 interaction resulted in late endosome and/or lysosome enlargement.
Fig. 5: The membrane interactions of the AP5–SPG11–SPG15 complex.
Fig. 6: Effect of AP5βtrunk–SPG11–SPG15, SPG11–SPG15 and AP5βtrunk–SPG11WD40-hairpin complexes on GUVs by fluorescence microscopy.

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Data availability

Cryo-EM density maps as well as masks were deposited in the Electron Microscopy Data Bank (EMDB), the coordinates were deposited in the PDB and the motion-corrected micrographs have been deposited in the EMPIAR. Accession codes are as follows: AP5βtrunk–SPG11–SPG15 (PDB 8YAB, EMD-39094, EMPIAR-12225), AP5FL–SPG11–SPG15 (PDB 8YAH, EMD-39099, EMPIAR-12220) and SPG11–SPG15 (PDB 8YAD, EMD-39096, EMPIAR-12221, EMPIAR-12222, EMPIAR-12223, EMPIAR-12224). The AlphaFold2 models are available in ModelArchive (modelarchive.org) with the accession code ma-yc8cz. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD054972. Source data are provided with this paper.

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Acknowledgements

We thank C.-Y. Lim at Guangzhou National Laboratory for the gift of the TMEM192 cell line. We thank the cryo-EM (KEMC) and advanced mass spectrometry facility (KMS) of Kobilka Institute of Innovative Drug Discovery, the Chinese University of Hong Kong (Shenzhen). This work was supported by the Stable Support Plan Program of Shenzhen Natural Science Fund (to M.-Y.S., grant no. 20231120103446003), Guangdong Basic and Applied Basic Research Foundation (to M.-Y.S., grant nos. 2024A1515011683), the National Natural Science Foundation of China (grant no. 31950410540 to G.S.), Foreign Young Talent Program from State Administration of Foreign Experts Affairs (grant no. QN2021032004L to G.S.), Shenzhen Medical Research Fund (grant no. B2402014 to G.S.), CUHK-Shenzhen University Development Fund (to G.S.) and the Start-up funding from SUSTech (to M.-Y.S.). M.L. and X.W. were supported by a Ganghong Young Scholar Development Fund at the Chinese University of Hong Kong, Shenzhen. M.-Y.S. is an investigator of SUSTech Institute for Biological Electron Microscopy.

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Authors and Affiliations

  1. Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China

    Xinyi Mai, Yang Wang, Xi Wang, Ming Liu, Fei Teng, Zheng Liu & Goran Stjepanovic

  2. Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, China

    Fei Teng & Ming-Yuan Su

  3. Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen, China

    Ming-Yuan Su

  4. Institute for Biological Electron Microscopy, Southern University of Science and Technology, Shenzhen, China

    Ming-Yuan Su

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Contributions

X.M., M.-Y.S. and G.S. designed the experiments. X.M. and X.W. performed the experiments. X.M. and Y.W. collected the EM data. X.M., Y.W. and M.-Y.S. processed the EM data. F.T., M.L. and Z.L. contributed in the early stages of the project. M.-Y.S. and G.S. wrote the manuscript.

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Correspondence to Ming-Yuan Su or Goran Stjepanovic.

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Nature Structural & Molecular Biology thanks Richard Baker and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Katarzyna Ciazynska, in collaboration with the Nature Structural & Molecular Biology team.

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Extended data

Extended Data Fig. 1 Representative negative stain micrographs of SPG11-SPG15, AP5FL-SPG11- SPG15 and AP5βtrunk-SPG11-SPG15 complex.

The shape of the complex can be recognized and circled in the raw image. Schematic representation of SPG11-SPG15 (a), AP5FL-SPG11-SPG15 (b) and AP5βtrunk-SPG11-SPG15 (c) complexes used in the negative stain experiment are shown. Negative stain was repeated at least three times for each complex.

Extended Data Fig. 2 Overview of cryo-EM processing of human SPG11-SPG15.

a, Coomassie blue-stained SDS-PAGE of purified SPG11-SPG15. SDS-PAGE is representative of at least three independent experiments. MW, molecular weight. b, Representative motion-corrected cryo-EM micrograph (of 33,954 micrographs from 4 datasets) of the human SPG11-SPG15 complex. c, Representative 2D class averages for the SPG11-SPG15 complex. d, Flow chart of cryo-EM data processing. e, SPG11-SPG15 map color-coded by the local resolution estimation.

Extended Data Fig. 3 Negative stain analysis of SPG11-SPG15.

a, b, The 2D class averages and representative particles showing the dimeric SPG11-SPG15 and monomer SPG11-SPG15. c, The model of the AP5FL-SPG11-SPG15 complex fitted into the map.

Extended Data Fig. 4 Cryo-EM structure determination of the AP5FL-SPG11-SPG15.

a, Coomassie blue-stained SDS-PAGE of the purified AP5FL-SPG11-SPG15 complex. SDS-PAGE is representative of at least three independent experiments. MW, molecular weight. b, Representative motion-corrected cryo-EM micrograph (of 10,420 micrographs) of the AP5FL-SPG11-SPG15 complex. c, Representative 2D class averages for the AP5FL-SPG11-SPG15 complex. d, Flow chart of cryo-EM data processing. NU-refinement: nonuniform refinement. e, The FSC plots are between two independently refined half-maps with no mask (blue), spherical mask (orange), loose mask (green), tight mask (red), and corrected (purple). A cut-off of 0.143 (blue line) was used to estimate the resolution. f, Angular particle distribution calculated in cryoSPARC for particle projections. The heatmap shows the number of particles for each viewing angle. g, AP5FL-SPG11-SPG15 map color-coded by the local resolution estimation. h, The structure of the AP5β5 trunk in complex with the ζ trunk, the ζ trunk in complex with σ5 and the β5 trunk in complex with μ5. i, Open and compact conformation of the AP5 complex.

Extended Data Fig. 5 SPG11 is required for AP5 complex assembly.

a, Size exclusion profiles (Superdex 200 Increased 10/300 GL) of AP5ζ-σ5, AP5β5trunk-μ5 subcomplexes as well as incubation with SPG11WD40-hairpin (left). SDS-PAGE analysis of the peak fractions from the complexes (right). SDS-PAGE is representative of at least three independent experiments. MW, molecular weight. b, Pull-down experiment of MBP-SPG15, TSF-SPG11, GST-AP5β5trunk/μ5 and AP5ζ-GST/σ5. c, Pull-down experiment of MBP-SPG15, TSF-SPG11 and GST-AP5β5/μ5. The pull-down experiments were repeated three times. Schematic representation of SPG11-SPG15, AP5βtrunk-SPG11WD40-hairpin and AP5 subcomplexes are shown.

Source data

Extended Data Fig. 6 Cryo-EM structure determination of the AP5βtrunk-SPG11-SPG15 complex.

a, Representative motion-corrected cryo-EM micrograph (of 5,644 micrographs) of the AP5βtrunk-SPG11-SPG15 complex. b, Representative 2D class averages for the AP5βtrunk-SPG11-SPG15 complex. c, Flow chart of cryo-EM data processing. NU-refinement: nonuniform refinement. d, Angular particle distribution calculated in cryoSPARC for particle projections. The heatmap shows the number of particles for each viewing angle. e, The FSC plots are between two independently refined half-maps with no mask (blue), spherical mask (orange), loose mask (green), tight mask (red), and corrected (purple). A cut-off of 0.143 (blue line) was used to estimate the resolution. f, AP5βtrunk-SPG11-SPG15 map color-coded by the local resolution estimation.

Extended Data Fig. 7 Model to map fitting.

a, FSC between the model and map for SPG11-SPG15 against the cryo-EM map. b, FSC between the model and map for the AP5βtrunk-SPG11-SPG15 complex against the cryo-EM map. c, FSC between the model and map for the AP5FL-SPG11-SPG15 complex against the cryo-EM map. d, Representative cryo-EM densities fitted to the model.

Extended Data Fig. 8 SPG11 mutations associated with spastic paraplegia mapped onto the SPG11-SPG15 structure.

Many of the SPG11 mutations causative of spastic paraplegia are predicted to result in premature termination of peptide synthesis.

Extended Data Fig. 9 Structural comparison of the AP5 complex with AP1-3 complexes.

a, List of subunits in the four AP complexes including AP1-3 and AP5 complex. b, Conformational states for AP1-3 and AP5 complexes.

Extended Data Fig. 10 Structural comparison of the AP5 complex with the adaptor-like γ-ζ-β-δ- COP subcomplex of COPI complex.

AP5 is in super-open conformation with two arms of the complex measuring ~150 Å apart. Structure model of the extended γ-ζ-β-δ-COP subcomplex is shown for comparison (PDB ID 5NZT). The ear domains of γ-COP and β-COP as well as C-μ5 were removed for clarity.

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Mai, X., Wang, Y., Wang, X. et al. Structural basis for membrane remodeling by the AP5–SPG11–SPG15 complex. Nat Struct Mol Biol 32, 1334–1346 (2025). https://doi.org/10.1038/s41594-025-01500-0

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