Molecular Basis of Multiple Mitochondrial Dysfunctions Syndrome 2 Caused by CYS59TYR BOLA3 Mutation
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 nove...
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doaj-34107e13457649d99a126b6538c373d12021-05-31T23:08:39ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-05-01224848484810.3390/ijms22094848Molecular Basis of Multiple Mitochondrial Dysfunctions Syndrome 2 Caused by CYS59TYR BOLA3 MutationGiovanni Saudino0Dafne Suraci1Veronica Nasta2Simone Ciofi-Baffoni3Lucia Banci4Magnetic Resonance Center (CERM), University of Florence, 50019 Sesto Fiorentino, ItalyMagnetic Resonance Center (CERM), University of Florence, 50019 Sesto Fiorentino, ItalyMagnetic Resonance Center (CERM), University of Florence, 50019 Sesto Fiorentino, ItalyMagnetic Resonance Center (CERM), University of Florence, 50019 Sesto Fiorentino, ItalyMagnetic Resonance Center (CERM), University of Florence, 50019 Sesto Fiorentino, ItalyMultiple 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]<sup>2+</sup> 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.https://www.mdpi.com/1422-0067/22/9/4848BOLA3GLRX5multiple mitochondrial dysfunctions syndromeiron–sulfur proteinmitochondriaMMDS2 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Giovanni Saudino Dafne Suraci Veronica Nasta Simone Ciofi-Baffoni Lucia Banci |
spellingShingle |
Giovanni Saudino Dafne Suraci Veronica Nasta Simone Ciofi-Baffoni Lucia Banci Molecular Basis of Multiple Mitochondrial Dysfunctions Syndrome 2 Caused by CYS59TYR BOLA3 Mutation International Journal of Molecular Sciences BOLA3 GLRX5 multiple mitochondrial dysfunctions syndrome iron–sulfur protein mitochondria MMDS2 |
author_facet |
Giovanni Saudino Dafne Suraci Veronica Nasta Simone Ciofi-Baffoni Lucia Banci |
author_sort |
Giovanni Saudino |
title |
Molecular Basis of Multiple Mitochondrial Dysfunctions Syndrome 2 Caused by CYS59TYR BOLA3 Mutation |
title_short |
Molecular Basis of Multiple Mitochondrial Dysfunctions Syndrome 2 Caused by CYS59TYR BOLA3 Mutation |
title_full |
Molecular Basis of Multiple Mitochondrial Dysfunctions Syndrome 2 Caused by CYS59TYR BOLA3 Mutation |
title_fullStr |
Molecular Basis of Multiple Mitochondrial Dysfunctions Syndrome 2 Caused by CYS59TYR BOLA3 Mutation |
title_full_unstemmed |
Molecular Basis of Multiple Mitochondrial Dysfunctions Syndrome 2 Caused by CYS59TYR BOLA3 Mutation |
title_sort |
molecular basis of multiple mitochondrial dysfunctions syndrome 2 caused by cys59tyr bola3 mutation |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-05-01 |
description |
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]<sup>2+</sup> 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. |
topic |
BOLA3 GLRX5 multiple mitochondrial dysfunctions syndrome iron–sulfur protein mitochondria MMDS2 |
url |
https://www.mdpi.com/1422-0067/22/9/4848 |
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