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ISCA1 Orchestrates ISCA2 and NFU1 in the Maturation of Human Mitochondrial [4Fe-4S] Proteins |
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| Institution: | 1. Molecular Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA;1. Hospital Clínic, IDIBAPS, CIBERER, Barcelona, Spain;2. Clinica Universitária de Navarra, Facultad Medicina, Pamplona, Spain;3. Hospital Vall d''Hebron, UAB, Barcelona, Spain;4. Hospital Sant Joan de Deu, CIBERER, Barcelona, Spain;5. Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, United Kingdom;6. CSIC, Barcelona, Spain;1. Department of Chemistry and Biochemistry, The Ohio State University, 100 West 18th Avenue, Columbus, OH 43210, USA;2. The Ohio State Biochemistry Program, The Ohio State University, 484 W. 12th Ave, Columbus, OH, 43210, USA;3. The Biophysics Graduate Program, The Ohio State University, 484 W. 12th Ave, Columbus, OH, 43210, USA;1. Institut für Zytobiologie, Philipps-Universität Marburg, 35032 Marburg, Germany;2. Université de Lorraine, Inra, IAM, F-54000 Nancy, France;1. Lab. de Biotecnología Microbiana, Instituto de Investigaciones Químico Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Morelia, Michoacán, Mexico;2. Lab. de Bioquímica, Instituto de Investigaciones Químico Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Morelia, Michoacán, Mexico |
| 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. |
| Keywords: | iron-sulfur protein iron-sulfur cluster assembly machinery mitochondria NMR protein-protein interaction Fe-S"} {"#name":"keyword" "$":{"id":"k0035"} "$$":[{"#name":"text" "_":"Iron-sulfur HSQC"} {"#name":"keyword" "$":{"id":"k0045"} "$$":[{"#name":"text" "_":"Heteronuclear single quantum coherence SEC-MALS"} {"#name":"keyword" "$":{"id":"k0055"} "$$":[{"#name":"text" "_":"Size exclusion chromatography equipped with multiangle light scattering LB"} {"#name":"keyword" "$":{"id":"k0065"} "$$":[{"#name":"text" "_":"Luria-Bertani IPTG"} {"#name":"keyword" "$":{"id":"k0075"} "$$":[{"#name":"text" "_":"Isopropyl-β-D-1-thiogalactopyranoside BSA"} {"#name":"keyword" "$":{"id":"k0085"} "$$":[{"#name":"text" "_":"Bovine serum albumin DTT"} {"#name":"keyword" "$":{"id":"k0095"} "$$":[{"#name":"text" "_":"1 4-dithiothreitol |
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