Understanding the molecular basis of multiple mitochondrial dysfunctions syndrome 1 (MMDS1)—impact of a disease-causing Gly208Cys substitution on structure and activity of NFU1 in the Fe/S cluster biosynthetic pathway
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Iron-sulfur (Fe/S)-cluster-containing proteins constitute one of the largest protein classes, with varied functions that include electron transport, regulation of gene expression, substrate binding and activation, and radical generation. Consequently, the biosynthetic machinery for Fe/S clusters is evolutionarily conserved, and mutations in a variety of putative intermediate Fe/S cluster scaffold proteins can cause disease states, including multiple mitochondrial dysfunctions syndrome (MMDS), sideroblastic anemia, and mitochondrial encephalomyopathy. Herein, we have characterized the impact of defects occurring in the MMDS1 disease state that result from a point mutation (Gly208Cys) near the active site of NFU1, an Fe/S scaffold protein, via an in vitro investigation into the structural and functional consequences. Analysis of protein stability and oligomeric state demonstrates that the mutant increases the propensity to dimerize and perturbs the secondary structure composition. These changes appear to underlie the severely decreased ability of mutant NFU1 to accept an Fe/S cluster from physiologically relevant sources. Therefore, the point mutation on NFU1 impairs downstream cluster trafficking and results in the disease phenotype, because there does not appear to be an alternative in vivo reconstitution path, most likely due to greater protein oligomerization from a minor structural change.
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Mutations or dysfunctions of Fe-S cluster biogenesis have been linked to multiple inherited disorders such as Friedreich's ataxia, infantile complex II/III deficiency syndrome, and multiple mitochondrial dysfunctions syndromes.
“mutations or dysfunctions of Fe-S cluster biogenesis have been linked to multiple inherited disorders such as Friedreich's ataxia (caused by a disruptive guanine-adenine-adenine repeat in the first intron of FXN) (Campuzano et al., 1996), infantile complex II/III deficiency syndrome (a lethal autosomal recessive disease caused by a point mutation in NFS1) (Farhan et al., 2014) and multiple”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Wachnowsky et al., 2017
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The Role of Iron Regulation in Immunometabolism and Immune-Related Disease
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- Authors
- Wachnowsky, C., Wesley, N. A., Fidai, I., & Cowan, J. A.
- Affiliations
- The Ohio State University (US)
- Corresponding author
- Cowan, J.A.
- Venue
- Journal of Molecular Biology
- Publisher
- Elsevier BV
- Published
- 2017-03
- Volume
- 429
- Issue
- 6
- Pages
- 790-807
- ISSN
- 0022-2836 (ISSN-L)
- PMC
- PMC5466808
- OpenAlex
- W2583796359
- Cited by
- 25
- References
- 78
- Citations by year
- 2026: 1 · 2025: 1 · 2023: 2 · 2022: 2 · 2021: 4 · 2020: 4 · 2019: 3 · 2018: 2 · 2017: 6
- FWCI
- 1.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (T32GM095450)
- National Institute of Allergy and Infectious Diseases (R21AI072443)
- Topics
- Physical Sciences › Energy › Renewable Energy, Sustainability and the Environment › Metalloenzymes and iron-sulfur proteins
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- NFU1, iron-sulfur cluster assembly, protein dimerization, protein stability, secondary structure, sideroblastic anemia, mitochondrial encephalomyopathy, point mutations
- MeSH terms
- Carrier Proteins, Humans, Iron-Sulfur Proteins, Protein Structure, Secondary, Amino Acid Substitution, Mutation, Missense, Mitochondrial Diseases, Mutant Proteins, Biosynthetic Pathways, Protein Multimerization, Protein Stability
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