ISCA1 Orchestrates ISCA2 and NFU1 in the Maturation of Human Mitochondrial [4Fe-4S] Proteins

Year: 2021

Authors: Suraci D., Saudino G., Nasta V., Ciofi-Baffoni S., Banci L.

Autors Affiliation: Univ Florence, Magnet Resonance Ctr CERM, Via Luigi Sacconi 6, I-50019 Florence, Italy; Univ Florence, Dept Chem, Via Lastruccia 3, I-50019 Sesto Fiorentino, Italy.

Abstract: The late-acting steps of the pathway responsible for the maturation of mitochondrial [4Fe-4S] proteins are still elusive. Three proteins ISCA1, ISCA2 and NFU1 were shown to be implicated in the assembly of [4Fe-4S] clusters and their transfer into mitochondrial apo proteins. We present here a NMR-based study showing a detailed molecular model of the succession of events performed in a coordinated manner by ISCA1, ISCA2 and NFU1 to make [4Fe-4S] clusters available to mitochondrial apo proteins. We show that ISCA1 is the key player of the [4Fe-4S] protein maturation process because of its ability to interact with both NFU1 and ISCA2, which, instead do not interact each other. ISCA1 works as the promoter of the interaction between ISCA2 and NFU1 being able to determine the formation of a transient ISCA1-ISCA2-NFU1 ternary complex. We also show that ISCA1, thanks to its specific interaction with the C-terminal cluster-binding domain of NFU1, drives [4Fe-4S] cluster transfer from the site where the cluster is assembled on the ISCA1-ISCA2 complex to a cluster binding site formed by ISCA1 and NFU1 in the ternary ISCA1-ISCA2-NFU1 complex. Such mechanism guarantees that the [4Fe-4S] cluster can be safely moved from where it is assembled on the ISCA1-ISCA2 complex to NFU1, thereby resulting the [4Fe-4S] cluster available for the mitochondrial apo proteins specifically requiring NFU1 for their maturation. (C) 2021 Elsevier Ltd. All rights reserved.

Journal/Review: JOURNAL OF MOLECULAR BIOLOGY

Volume: 433 (10)      Pages from: 166924-1  to: 166924-17

More Information: The authors acknowledge funding from timb3 (grant number 810856) and iNEXT-Discovery, Grant Agreement No. 871037, both funded by the Horizon 2020 programme of the European Commission. Financial support of the Fondazione Cassa di Risparmio di Firenze (CRF2018.0920) is also gratefully acknowledged. Work at CERM is supported by the Italian Ministry for University and Research (FOE funding) to the Italian Center (CERM, University of Florence) of Instruct-ERIC, a European Research Infrastructure, ESFRI Landmark. This article is based upon work from COST Action CA15133, supported by COST (European Cooperation in Science and Technology).
KeyWords: iron-sulfur protein; iron-sulfur cluster assembly machinery; mitochondria; NMR; protein-protein interaction
DOI: 10.1016/j.jmb.2021.166924