Revisiting the Role of the Leucine Plug/Valve in the Human ABCG2 Multidrug Transporter

• DOI: 10.20944/preprints202503.1238.v1
• Publication Date: 2025-03-20T01:14:06Z
• Authors: Orsolya Mózner; Kata Sára Szabó; Anikó Bodnár; Csenge Koppány; László Homolya; György Várady; Tamás Hegedűs; Balázs Sarkadi; Ágnes Telbisz
• Keywords: Abcg2

In the human ABCG2 multidrug transporter a so called “leucin plug/valve” (aa. L554/L555) has been suggested to determine substrate exit and coupling of drug transport ATPase activity. this work we have analyzed effects selected var-iants in region by expressing these variants both mammalian Sf9 insect cells. We found that cells L554A, L554F, L555F combination L554F/L555F were functional, processed plasma membrane, exhibited activity similar wild-type ABCG2, while L555A L554A/L555A mutants poorly expressed mam-malian cells, all at levels, still, lost transport-related function, L554F had reduced dye altered sub-strate-stimulated molecular dynamics simulations mutant highly rearranged contacts central transmembrane helices, thus alterations folding, trafficking function can be expected occur. Our cur-rent studies reinforce importance L554/L555 folding do not support specific role selective handling show general reduction