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The lysosomal transporter TAPL has a dual role as peptide translocator and phosphatidylserine floppase

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  • Jun Gyou Park

    (Gwangju Institute of Science and Technology (GIST))

  • Songwon Kim

    (Gwangju Institute of Science and Technology (GIST))

  • Eunhong Jang

    (Gwangju Institute of Science and Technology (GIST))

  • Seung Hun Choi

    (Gwangju Institute of Science and Technology (GIST))

  • Hyunsu Han

    (Gwangju Institute of Science and Technology (GIST))

  • Seulgi Ju

    (Gwangju Institute of Science and Technology (GIST))

  • Ji Won Kim

    (Pohang University of Science and Technology (POSTECH))

  • Da Sol Min

    (Gwangju Institute of Science and Technology (GIST))

  • Mi Sun Jin

    (Gwangju Institute of Science and Technology (GIST))

Abstract

TAPL is a lysosomal ATP-binding cassette transporter that translocates a broad spectrum of polypeptides from the cytoplasm into the lysosomal lumen. Here we report that, in addition to its well-known role as a peptide translocator, TAPL exhibits an ATP-dependent phosphatidylserine floppase activity that is the possible cause of its high basal ATPase activity and of the lack of coupling between ATP hydrolysis and peptide efflux. We also present the cryo-EM structures of mouse TAPL complexed with (i) phospholipid, (ii) cholesteryl hemisuccinate (CHS) and 9-mer peptide, and (iii) ADP·BeF3. The inward-facing structure reveals that F449 protrudes into the cylindrical transport pathway and divides it into a large hydrophilic central cavity and a sizable hydrophobic upper cavity. In the structure, the peptide binds to TAPL in horizontally-stretched fashion within the central cavity, while lipid molecules plug vertically into the upper cavity. Together, our results suggest that TAPL uses different mechanisms to function as a peptide translocase and a phosphatidylserine floppase.

Suggested Citation

  • Jun Gyou Park & Songwon Kim & Eunhong Jang & Seung Hun Choi & Hyunsu Han & Seulgi Ju & Ji Won Kim & Da Sol Min & Mi Sun Jin, 2022. "The lysosomal transporter TAPL has a dual role as peptide translocator and phosphatidylserine floppase," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33593-2
    DOI: 10.1038/s41467-022-33593-2
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    References listed on IDEAS

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