MitoNEET is a uniquely folded 2Fe 2S outer mitochondrial membrane protein stabilized by pioglitazone.
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.
Paddock
Mark L
ML
Department of Physics, University of California at San Diego, La Jolla, CA 92093, USA.
Wiley
Sandra E
SE
Axelrod
Herbert L
HL
Cohen
Aina E
AE
Roy
Melinda
M
Abresch
Edward C
EC
Capraro
Dominique
D
Murphy
Anne N
AN
Nechushtai
Rachel
R
Dixon
Jack E
JE
Jennings
Patricia A
PA
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*
C525595:CISD1 protein, human; D033862:Iron-Binding Proteins; D007506:Iron-Sulfur Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D045162:Thiazolidinediones; D000077205:Pioglitazone