title: MitoNEET is a uniquely folded 2Fe 2S outer mitochondrial membrane protein stabilized by pioglitazone.
abstract: Iron-sulfur (Fe-S) proteins are key players in vital processes involving energy homeostasis and metabolism from the simplest to most complex organisms. We report a 1.5 A x-ray crystal structure of the first identified outer mitochondrial membrane Fe-S protein, mitoNEET. Two protomers intertwine to form a unique dimeric structure that constitutes a new fold to not only the approximately 650 reported Fe-S protein structures but also to all known proteins. We name this motif the NEET fold. The protomers form a two-domain structure: a beta-cap domain and a cluster-binding domain that coordinates two acid-labile 2Fe-2S clusters. Binding of pioglitazone, an insulin-sensitizing thiazolidinedione used in the treatment of type 2 diabetes, stabilizes the protein against 2Fe-2S cluster release. The biophysical properties of mitoNEET suggest that it may participate in a redox-sensitive signaling and/or in Fe-S cluster transfer.
authors.affiliation: Department of Physics, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Paddock
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Wiley
authors.forename: Herbert L
authors.initials: HL
authors.lastname: Axelrod
authors.forename: Aina E
authors.initials: AE
authors.lastname: Cohen
authors.forename: Melinda
authors.initials: M
authors.lastname: Roy
authors.forename: Edward C
authors.initials: EC
authors.lastname: Abresch
authors.forename: Dominique
authors.initials: D
authors.lastname: Capraro
authors.forename: Anne N
authors.initials: AN
authors.lastname: Murphy
authors.forename: Rachel
authors.initials: R
authors.lastname: Nechushtai
authors.forename: Jack E
authors.initials: JE
authors.lastname: Dixon
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Jennings
mesh_terms: D018360:Crystallography, X-Ray; D006801:Humans; D033862:Iron-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D007506:Iron-Sulfur Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D000077205:Pioglitazone; D011485:Protein Binding; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D045162:Thiazolidinediones / Q000737:chemistry*
chemical_list: C525595:CISD1 protein, human; D033862:Iron-Binding Proteins; D007506:Iron-Sulfur Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D045162:Thiazolidinediones; D000077205:Pioglitazone