Analysis of NFU-1 metallocofactor binding-site substitutions-impacts on iron-sulfur cluster coordination and protein structure and function
| Autor: | Insiya Fidai, Nathaniel A. Wesley, James A. Cowan, Christine Wachnowsky |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Scaffold protein Mitochondrial Diseases Stereochemistry Protein Conformation Iron Iron–sulfur cluster Biochemistry 03 medical and health sciences chemistry.chemical_compound Metalloprotein Missense mutation Humans Binding site Protein Dimerization Molecular Biology chemistry.chemical_classification Binding Sites 030102 biochemistry & molecular biology Cell Biology Ligand (biochemistry) 030104 developmental biology chemistry Mutation Mutagenesis Site-Directed Protein Multimerization Carrier Proteins Sulfur Cysteine |
| Zdroj: | The FEBS journal. 284(22) |
| ISSN: | 1742-4658 |
| Popis: | Iron-sulfur (Fe/S) clusters are ancient prosthetic groups found in numerous metalloproteins and are conserved across all kingdoms of life due to their diverse, yet essential functional roles. Genetic mutations to a specific subset of mitochondrial Fe/S cluster delivery proteins are broadly categorized as disease-related under multiple mitochondrial dysfunction syndrome (MMDS), with symptoms indicative of a general failure of the metabolic system. Multiple mitochondrial dysfunction syndrome 1 (MMDS1) arises as a result of the missense mutation in NFU1, an Fe/S cluster scaffold protein, which substitutes a glycine near the Fe/S cluster-binding pocket to a cysteine (p.Gly208Cys). This substitution has been shown to promote protein dimerization such that cluster delivery to NFU1 is blocked, preventing downstream cluster trafficking. However, the possibility of this additional cysteine, located adjacent to the cluster-binding site, serving as an Fe/S cluster ligand has not yet been explored. To fully understand the consequences of this Gly208Cys replacement, complementary substitutions at the Fe/S cluster-binding pocket for native and Gly208Cys NFU1 were made, along with six other variants. Herein, we report the results of an investigation on the effect of these substitutions on both cluster coordination and NFU1 structure and function. The data suggest that the G208C substitution does not contribute to cluster binding. Rather, replacement of the glycine at position 208 changes the oligomerization state as a result of global structural alterations that result in the downstream effects manifest as MMDS1, but does not perturb the coordination chemistry of the Fe-S cluster. |
| Databáze: | OpenAIRE |
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