[대학원 생명과학과 세미나 안내]
연사 : 진미선 교수(광주과학기술원 생명과학부)
연제 : The lysosomal transporter TAPL has a dual role as peptide translocator and lipid floppase
일시 : 2021년 10월 01일 (금) 오후 5시
장소 : 온라인 화상 강의로 진행됩니다.
초청교수 : 송현규 교수
Abstract
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•BeF3-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. Both the N- and C-termini of a bound peptide are attached to the transporter by hydrogen bonds via the strictly-conserved Y405 residue in each monomer, whereas the central peptide region forms only minor contacts with the transporter. Lipid molecules plug vertically into the upper cavity where their head groups project toward the apex of the transport pathway. Binding of ADP•BeF3 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.