Crystal Structures of Nucleotide-Free and Glutathione-Bound Mitochondrial ABC Transporter Atm1

Abstract

The yeast mitochondrial ABC transporter Atm1, in concert with glutathione, functions in the export of a substrate required for cytosolic-nuclear iron-sulfur protein biogenesis and cellular iron regulation. Defects in the human ortholog ABCB7 cause the sideroblastic anemia XLSA/A. Here, we report the crystal structures of free and glutathione-bound Atm1 in inward-facing, open conformations at 3.06- and 3.38-angstrom resolution, respectively. The glutathione binding site includes a residue mutated in XLSA/A and is located close to the inner membrane surface in a large cavity. The two nucleotide-free adenosine 5'-triphosphate binding domains do not interact yet are kept in close vicinity through tight interaction of the two C-terminal α-helices of the Atm1 dimer. The resulting protein stabilization may be a common structural feature of all ABC exporters.

Defects in a New Class of Sulfate/Anion Transporter Link Sulfur Acclimation Responses to Intracellular Glutathione Levels and Cell Cycle Control

“…4C; Table III). A plausible transport function for SMT15 might be in maintaining metal ion homeostasis through its function as a cotransporter (Lee et al, 2014;Srinivasan et al, 2014). Glutathione binds to and helps detoxify heavy metals and typically accumulates in response to elevated metals (Cobbett and Goldsbrough, 2002;Jozefczak et al, 2012;Zagorchev et al, 2013), so its elevated levels in smt15-1 could reflect a response to altered metal ion levels.…”

Structural basis for the mechanism of ABC transporters

“…Despite the clinical importance of human ABC transporters, only one structure has been reported, ABCB10, that is involved in erythropoiesis [23]. Eukaryotic structures homologous to human ABC transporters have been elucidated including P-gp from mouse [7,24] and Caenorhabditis elegans [25], Atm1 from Saccharomyces cerevisiae [26] and from Cyanidioschyzon merolae [27]. All eukaryotic ABC exporters have been crystallized in the same inward-facing state.…”

“…The structures of Sav1866 and MsbA [6,20] The only structural information between an ABC exporter and its substrate is from the crystal structure of the bacterial NaAtm1 [21] and eukaryotic Atm1 from S. cerevisiae [26] in complex with glutathione derivatives. The structure is in an inward-facing conformation and TMs 4-6 provide key interactions with the glutathione derivatives.…”

Mitochondrial Iron-Sulfur Cluster Activity and Cytosolic Iron Regulate Iron Traffic in Saccharomyces cerevisiae

“…2). Atm1, an ATP-binding cassette half-transporter on the inner membrane of mitochondria, is thought to export a sulfur-containing by-product of ISC assembly called "X-S" (24,25). The identity of X-S is unknown, but it is thought to pass through a cavity sized for a small metabolite such as glutathione persulfide (26).…”