Molecular Basis of Multiple Mitochondrial Dysfunctions Syndrome 2 Caused by CYS59TYR BOLA3 Mutation
| Autor: | Dafne Suraci, Veronica Nasta, Simone Ciofi-Baffoni, Lucia Banci, Giovanni Saudino |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Iron-Sulfur Proteins
0301 basic medicine Mitochondrial Diseases QH301-705.5 iron–sulfur protein Mitochondrion Compound heterozygosity Article Catalysis Mitochondrial Proteins Inorganic Chemistry 03 medical and health sciences 0302 clinical medicine Humans Cysteine Physical and Theoretical Chemistry Biology (General) Nuclear Magnetic Resonance Biomolecular Molecular Biology Gene QD1-999 Glutaredoxins Spectroscopy Genetics Chemistry Organic Chemistry General Medicine Ligand (biochemistry) Phenotype multiple mitochondrial dysfunctions syndrome 3. Good health Computer Science Applications Molecular Docking Simulation mitochondria 030104 developmental biology GLRX5 Multiprotein Complexes MMDS2 Mutation Mutation (genetic algorithm) BOLA3 030217 neurology & neurosurgery Biogenesis |
| Zdroj: | International Journal of Molecular Sciences, Vol 22, Iss 4848, p 4848 (2021) International Journal of Molecular Sciences Volume 22 Issue 9 |
| ISSN: | 1661-6596 1422-0067 |
| Popis: | Multiple mitochondrial dysfunctions syndrome (MMDS) is a rare neurodegenerative disorder associated with mutations in genes with a vital role in the biogenesis of mitochondrial [4Fe–4S] proteins. Mutations in one of these genes encoding for BOLA3 protein lead to MMDS type 2 (MMDS2). Recently, a novel phenotype for MMDS2 with complete clinical recovery was observed in a patient containing a novel variant (c.176G > A, p.Cys59Tyr) in compound heterozygosity. In this work, we aimed to rationalize this unique phenotype observed in MMDS2. To do so, we first investigated the structural impact of the Cys59Tyr mutation on BOLA3 by NMR, and then we analyzed how the mutation affects both the formation of a hetero-complex between BOLA3 and its protein partner GLRX5 and the iron–sulfur cluster-binding properties of the hetero-complex by various spectroscopic techniques and by experimentally driven molecular docking. We show that 1) the mutation structurally perturbed the iron–sulfur cluster-binding region of BOLA3, but without abolishing [2Fe–2S]2+ cluster-binding on the hetero-complex 2) tyrosine 59 did not replace cysteine 59 as iron–sulfur cluster ligand and 3) the mutation promoted the formation of an aberrant apo C59Y BOLA3–GLRX5 complex. All these aspects allowed us to rationalize the unique phenotype observed in MMDS2 caused by Cys59Tyr mutation. |
| Databáze: | OpenAIRE |
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