[초청강연] The lysosomal ABC transporter TAPL has a dual role as peptide translocase and lipid floppase

The lysosomal ABC transporter TAPL has a dual role as peptide

translocase and lipid floppase

Jun amp; Mi Sun Jin*

1 School of Life Sciences, GIST, 123 Cheomdan-gwagiro, Buk-gu, Gwangju 61005,
2 Department of Life Sciences, POSTECH, Nam-gu, Pohang 37673, Republic of Korea

TAPL is a lysosomal ATP-binding cassette transporter that uses the energy of ATP hydrolysis
to transport a broad spectrum of polypeptides from the cytoplasm into the lysosomal lumen.
Here we present the first cryo-EM structures of mouse TAPL in phosphoethanolamine (PE)-
bound, both cholesteryl hemisuccinate (CHS)- and peptide-bound, and ADP·BeF 3 -bound
states. Remarkably, in addition to its role as a peptide translocator, TAPL exhibits an ATP-
dependent lipid 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. 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. The peptide binds
to TAPL in horizontally-stretched fashion within the central cavity. Lipid molecules plug
vertically into the upper cavity where their head groups project toward the apex of the
transport pathway. Binding of ADP·BeF 3 to the cytoplasmic nucleotide-binding domains
reconfigures the overall transmembrane helices and opens the transport pathway to the
lysosomal lumen or the luminal leaflet of the lipid bilayer. Together, our results suggest that
TAPL uses different mechanisms to function as a peptide translocase and a lipid floppase.