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Structure of the human monomeric NEET protein MiNT and its role in regulating iron and reactive oxygen species in cancer cells
- Source :
- Proceedings of the National Academy of Sciences of the United States of America, vol 115, iss 2
- Publication Year :
- 2017
- Publisher :
- National Academy of Sciences, 2017.
-
Abstract
- The NEET family is a relatively new class of three related [2Fe-2S] proteins (CISD1–3), important in human health and disease. While there has been growing interest in the homodimeric gene products of CISD1 (mitoNEET) and CISD2 (NAF-1), the importance of the inner mitochondrial CISD3 protein has only recently been recognized in cancer. The CISD3 gene encodes for a monomeric protein that contains two [2Fe-2S] CDGSH motifs, which we term mitochondrial inner NEET protein (MiNT). It folds with a pseudosymmetrical fold that provides a hydrophobic motif on one side and a relatively hydrophilic surface on the diametrically opposed surface. Interestingly, as shown by molecular dynamics simulation, the protein displays distinct asymmetrical backbone motions, unlike its homodimeric counterparts that face the cytosolic side of the outer mitochondrial membrane/endoplasmic reticulum (ER). However, like its counterparts, our biological studies indicate that knockdown of MiNT leads to increased accumulation of mitochondrial labile iron, as well as increased mitochondrial reactive oxygen production. Taken together, our study suggests that the MiNT protein functions in the same pathway as its homodimeric counterparts (mitoNEET and NAF-1), and could be a key player in this pathway within the mitochondria. As such, it represents a target for anticancer or antidiabetic drug development.
- Subjects :
- 0301 basic medicine
Iron-Sulfur Proteins
Protein Folding
1.1 Normal biological development and functioning
Iron
Mitochondrion
Molecular Dynamics Simulation
Crystallography, X-Ray
Cell Line
Mitochondrial Proteins
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Protein Domains
Underpinning research
Cell Line, Tumor
Neoplasms
cancer
Humans
Gene
chemistry.chemical_classification
Reactive oxygen species
Gene knockdown
Multidisciplinary
Tumor
Crystallography
Endoplasmic reticulum
Cell biology
mitochondria
Cytosol
Kinetics
030104 developmental biology
Monomer
chemistry
Cancer cell
Physical Sciences
Mitochondrial Membranes
Mutation
X-Ray
iron homeostasis
RNA Interference
Generic health relevance
NEET proteins
Reactive Oxygen Species
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America, vol 115, iss 2
- Accession number :
- edsair.doi.dedup.....93876ba25546c331a02e25a76ed9d1af