biostudies-literatureAdolf LAFortuene Program University Hospital TuebingenDeutsche ForschungsgemeinschaftSpanish Ministry of ScienceGerman Center of Infection Researche85304https://www.ebi.ac.uk/biostudies/studies/S-EPMC10147376biostudies-literatureUnknown12Sufficient access to transition metals such as iron is essential for bacterial proliferation and their active limitation within host tissues effectively restricts infection. To overcome iron limitation, the invasive pathogen <i>Staphylococcus aureus</i> uses the iron-regulated surface determinant (Isd) system to acquire hemoglobin-derived heme. While heme transport over the cell wall is well understood, its transport over the membrane is hardly investigated. In this study, we show the heme-specific permease IsdF to be energized by the general ATPase FhuC. Additionally, we show that IsdF needs appropriate location within the membrane for functionality. The membrane of <i>S. aureus</i> possesses special compartments (functional membrane microdomains [FMMs]) to organize membrane complexes. WeeLifeFunctional membrane microdomains and the hydroxamate siderophore transporter ATPase FhuC govern Isd-dependent heme acquisition in <i>Staphylococcus aureus</i>.PMC10147376398967434 -TRR2612507-0-0EXC 2124 - 390838134PID2020-115699GB-100TTU 08.708_00Kricks LGrein FMuller-Jochim AHeilbronner SAdolf LALopez DPuls JSfalseFunctional membrane microdomains and the hydroxamate siderophore transporter ATPase FhuC govern Isd-dependent heme acquisition in <i>Staphylococcus aureus</i>.Sufficient access to transition metals such as iron is essential for bacterial proliferation and their active limitation within host tissues effectively restricts infection. To overcome iron limitation, the invasive pathogen <i>Staphylococcus aureus</i> uses the iron-regulated surface determinant (Isd) system to acquire hemoglobin-derived heme. While heme transport over the cell wall is well understood, its transport over the membrane is hardly investigated. In this study, we show the heme-specific permease IsdF to be energized by the general ATPase FhuC. Additionally, we show that IsdF needs appropriate location within the membrane for functionality. The membrane of <i>S. aureus</i> possesses special compartments (functional membrane microdomains [FMMs]) to organize membrane complexes. We2023-01-01T00:00:00Z2023 Apr2025-04-04T19:18:31.13Z2025-04-04T19:18:31.13ZS-EPMC101473763704264010.7554/eLife.85304