Episodic mitochondrial myopathy with or without optic atrophy and reversibleleukoencephalopathy (MEOAL) is a rare, orphan autosomal recessive disordercaused by mutations in ferredoxin-2 (FDX2), which is a [2Fe-2S] cluster-binding protein participating in the formation of iron–sulfur clusters in mito-chondria. In this biosynthetic pathway, FDX2 works as electron donor to pro-mote the assembly of both [2Fe-2S] and [4Fe-4S] clusters. A recently identifiedmissense mutation of MEOAL is the homozygous mutation c.431C>T(p.P144L) described in six patients from two unrelated families. This mutationalters a highly conserved proline residue located in a loop of FDX2 that is dis-tant from the [2Fe-2S] cluster. How this Pro to Leu substitution damages iron–sulfur cluster biosynthesis is unknown. In this work, we have first comparedthe structural, dynamic, cluster binding and redox properties of WT and P144L[2Fe-2S] FDX2 to have clues on how the pathogenic P144L mutation can per-turb the FDX2 function. Then, we have investigated the interaction of bothWT and P144L [2Fe-2S] FDX2 with its physiological electron donor, ferredoxinreductase FDXR, comparing their electron transfer efficiency and protein–protein recognition patterns. Overall, the data indicate that the pathogenicP144L mutation negatively affects the FDXR-dependent electron transfer path-way from NADPH to FDX2, thereby reducing the capacity of FDX2 in assem-bling both [2Fe-2S] and [4Fe-4S] clusters. Our study also provided solidmolecular evidences on the functional role of the C-terminal tail of FDX2 inthe electron transfer between FDX2 and FDXR.
Unraveling the molecular determinants of a rare human mitochondrial disorder caused by the P144L mutation of FDX2
Doni, Davide;Costantini, Paola;
2024
Abstract
Episodic mitochondrial myopathy with or without optic atrophy and reversibleleukoencephalopathy (MEOAL) is a rare, orphan autosomal recessive disordercaused by mutations in ferredoxin-2 (FDX2), which is a [2Fe-2S] cluster-binding protein participating in the formation of iron–sulfur clusters in mito-chondria. In this biosynthetic pathway, FDX2 works as electron donor to pro-mote the assembly of both [2Fe-2S] and [4Fe-4S] clusters. A recently identifiedmissense mutation of MEOAL is the homozygous mutation c.431C>T(p.P144L) described in six patients from two unrelated families. This mutationalters a highly conserved proline residue located in a loop of FDX2 that is dis-tant from the [2Fe-2S] cluster. How this Pro to Leu substitution damages iron–sulfur cluster biosynthesis is unknown. In this work, we have first comparedthe structural, dynamic, cluster binding and redox properties of WT and P144L[2Fe-2S] FDX2 to have clues on how the pathogenic P144L mutation can per-turb the FDX2 function. Then, we have investigated the interaction of bothWT and P144L [2Fe-2S] FDX2 with its physiological electron donor, ferredoxinreductase FDXR, comparing their electron transfer efficiency and protein–protein recognition patterns. Overall, the data indicate that the pathogenicP144L mutation negatively affects the FDXR-dependent electron transfer path-way from NADPH to FDX2, thereby reducing the capacity of FDX2 in assem-bling both [2Fe-2S] and [4Fe-4S] clusters. Our study also provided solidmolecular evidences on the functional role of the C-terminal tail of FDX2 inthe electron transfer between FDX2 and FDXR.File | Dimensione | Formato | |
---|---|---|---|
Protein Science - 2024 - Grifagni - Unraveling the molecular determinants of a rare human mitochondrial disorder caused by.pdf
accesso aperto
Tipologia:
Published (publisher's version)
Licenza:
Creative commons
Dimensione
4.47 MB
Formato
Adobe PDF
|
4.47 MB | Adobe PDF | Visualizza/Apri |
Pubblicazioni consigliate
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.