Understanding the molecular basis for multiple mitochondrial dysfunctions syndrome 1 (MMDS1): impact of a disease-causing Gly189Arg substitution on NFU1
| Autor: | Insiya Fidai, Nathaniel A. Wesley, James A. Cowan, Christine Wachnowsky |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Scaffold protein Mitochondrial Diseases Protein Conformation Mitochondrial disease Iron Iron–sulfur cluster 010402 general chemistry 01 natural sciences Biochemistry Article 03 medical and health sciences chemistry.chemical_compound Biosynthesis medicine Humans Molecular Biology Binding Sites biology Point mutation Active site Cell Biology medicine.disease In vitro 0104 chemical sciences Cell biology Mitochondria 030104 developmental biology chemistry Mutation biology.protein Mutagenesis Site-Directed Protein Multimerization Carrier Proteins Function (biology) Sulfur |
| Zdroj: | The FEBS journal. 284(22) |
| ISSN: | 1742-4658 |
| Popis: | Iron-sulfur (Fe/S) cluster-containing proteins constitute one of the largest protein classes, with highly-varied function. Consequently, the biosynthesis of Fe/S clusters is evolutionarily conserved and mutations in intermediate Fe/S cluster scaffold proteins can cause disease, including multiple mitochondrial dysfunctions syndrome (MMDS). Herein, we have characterized the impact of defects occurring in the MMDS1 disease state that result from a point mutation (p.Gly189Arg) near the active site of NFU1, an iron-sulfur scaffold protein. In vitro investigation into the structure-function relationship of the Gly189Arg derivative, along with two other variants, reveals that substitution at position 189 triggers structural changes that increase flexibility, decrease stability, and alter the monomer-dimer equilibrium toward monomer, thereby impairing the ability of the Gly189X derivatives to receive an Fe/S cluster from physiologically-relevant sources. |
| Databáze: | OpenAIRE |
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