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Protein-Interaction Affinity Gradient Drives [4Fe-4S] Cluster Insertion in Human Lipoyl Synthase
Giovanni Saudino1, Simone Ciofi-Baffoni1,2, Lucia Banci1,2,3
1Magnetic Resonance Center (CERM), University of Florence, Via L. Sacconi 6, 50019 Sesto Fiorentino, Italy.
Journal of the American Chemical Society
|March 28, 2022
Summary
NFU1 and ISCA1 form a complex to insert iron-sulfur clusters into human lipoyl synthase (LIAS), a key step in lipoate biosynthesis. The NFU1 C-domain guides this crucial cluster transfer.
Area of Science:
- Mitochondrial biology
- Protein biochemistry
- Enzymology
Background:
- Human lipoyl synthase (LIAS) is essential for lipoate cofactor biosynthesis, utilizing two iron-sulfur ([4Fe-4S]) clusters.
- The precise mechanism of [4Fe-4S] cluster insertion into LIAS has remained largely unknown.
- Mitochondrial iron-sulfur cluster assembly machinery involves proteins like NFU1 and ISCA1.
Purpose of the Study:
- To elucidate the mechanism of [4Fe-4S] cluster insertion into the FeSRS site of human LIAS.
- To identify the key protein factors responsible for this essential biological process.
Main Methods:
- Investigated the interaction between NFU1, ISCA1, and LIAS.
- Characterized the role of the NFU1 C-domain in iron-sulfur cluster transfer.
- Analyzed the protein-interaction affinity gradient driving cluster insertion.
Main Results:
- NFU1 and ISCA1 form a heterodimeric complex that facilitates [4Fe-4S] cluster insertion into LIAS.
- The C-domain of NFU1 is critical for directing the [4Fe-4S] cluster to the FeSRS site.
- A protein-interaction affinity gradient from ISCA1 to LIAS, mediated by NFU1, drives the cluster transfer.
Conclusions:
- NFU1 and ISCA1 are essential components of the mitochondrial machinery for LIAS [4Fe-4S] cluster insertion.
- The NFU1 C-domain acts as a molecular guide, utilizing an affinity gradient to ensure correct cluster delivery.
- This study reveals a novel mechanism for iron-sulfur cluster trafficking in human cells.
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