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Peer-reviewedCC BY 4.0Nature Chemical Biology

Topogenic sequence recognition at TIM complexes revealed by a stendomycin-bound structure

  • Yuanyuan Chen1,2
  • Antony Lurie1,2
  • Kevin Wu1,2
  • Kihong Nam3
  • Samantha N. Garcia1,2
  • Nathaniel W. M. Dempsey1,2
  • Esben B. Svenningsen4
  • Thomas Tørring5
  • Thomas B. Poulsen4
  • Alban Ordureau3
  • Eunyong Park1,2
5 affiliations
  1. 1Department of Molecular and Cell Biology, University of California, Berkeley, CA USA
  2. 2California Institute for Quantitative Biosciences, University of California, Berkeley, CA USA
  3. 3Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY USA
  4. 4Department of Chemistry, Aarhus University, Aarhus, Denmark
  5. 5Department of Biological and Chemical Engineering, Aarhus University, Aarhus, Denmark
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Abstract

In the mitochondrial inner membrane (IM), topogenesis of imported proteins is mediated by TIM23 and TIM22 complexes. TIM23 translocates soluble polypeptides across the IM into the matrix, whereas TIM22 inserts polytopic membrane proteins into the IM. Although functionally distinct, both rely on homologous subunits, Tim17 in TIM23 and Tim22 in TIM22. The underlying mechanisms, however, remain elusive. Here we use structural and functional approaches with yeast Tim17, Tim22 and the TIM23 inhibitor stendomycin. Cryogenic-electron microscopy shows that stendomycin binds to the protein translocation cavity of Tim17, mimicking α-helical topogenic sequences. While Tim22 does not bind stendomycin, a single mutation in its equivalent cavity suffices to enable binding. The cavities of Tim17 and Tim22 are largely interchangeable without disrupting their functions. Lastly, stendomycin triggers a collapse of the membrane potential, likely via its Tim17- or Tim22-dependent translocation across the IM. These findings reveal a mechanistic overlap between protein translocases and insertases.

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Cite

BibTeXRIS
BibTeX
@article{chen2026topogenic,
  title = {{Topogenic sequence recognition at TIM complexes revealed by a stendomycin-bound structure}},
  author = {Yuanyuan Chen and Antony Lurie and Kevin Wu and Kihong Nam and Samantha N. Garcia and Nathaniel W. M. Dempsey and Esben B. Svenningsen and Thomas Tørring and Thomas B. Poulsen and Alban Ordureau and Eunyong Park},
  journal = {Nature Chemical Biology},
  year = {2026},
  month = aug,
  doi = {10.1038/s41589-026-02304-z},
  url = {https://doi.org/10.1038/s41589-026-02304-z},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Topogenic sequence recognition at TIM complexes revealed by a stendomycin-bound structure
AU  - Yuanyuan Chen
AU  - Antony Lurie
AU  - Kevin Wu
AU  - Kihong Nam
AU  - Samantha N. Garcia
AU  - Nathaniel W. M. Dempsey
AU  - Esben B. Svenningsen
AU  - Thomas Tørring
AU  - Thomas B. Poulsen
AU  - Alban Ordureau
AU  - Eunyong Park
PY  - 2026
DA  - 2026/08/26
JO  - Nature Chemical Biology
DO  - 10.1038/s41589-026-02304-z
UR  - https://doi.org/10.1038/s41589-026-02304-z
AB  - In the mitochondrial inner membrane (IM), topogenesis of imported proteins is mediated by TIM23 and TIM22 complexes. TIM23 translocates soluble polypeptides across the IM into the matrix, whereas TIM22 inserts polytopic membrane proteins into the IM. Although functionally distinct, both rely on homologous subunits, Tim17 in TIM23 and Tim22 in TIM22. The underlying mechanisms, however, remain elusive. Here we use structural and functional approaches with yeast Tim17, Tim22 and the TIM23 inhibitor stendomycin. Cryogenic-electron microscopy shows that stendomycin binds to the protein translocation cavity of Tim17, mimicking α-helical topogenic sequences. While Tim22 does not bind stendomycin, a single mutation in its equivalent cavity suffices to enable binding. The cavities of Tim17 and Tim22 are largely interchangeable without disrupting their functions. Lastly, stendomycin triggers a collapse of the membrane potential, likely via its Tim17- or Tim22-dependent translocation across the IM. These findings reveal a mechanistic overlap between protein translocases and insertases.
SN  - 1552-4450
SN  - 1552-4469
ER  -