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Human Mitochondrial NFS1-FXN XL LS-MS/MS

ABSTRACT: Frataxin (FXN) is involved in mitochondrial iron-sulfur (Fe-S) cluster biogenesis and serves to accelerate Fe-S cluster formation. FXN deficiency is associated with Friedreich ataxia, a neurodegenerative disease. Using chemical cross-linking (XL) accompanied with LC-MS/MS, we studied the the interaction between the core complexes Acp-ISD11-NFS1 (AIN) and AIN-ISCU (AINU) with FXN.

INSTRUMENT(S): 6340 Ion Trap LC/MS

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Cell

DISEASE(S): Friedreich Ataxia

SUBMITTER: Kai Cai

LAB HEAD: John L. Markley

PROVIDER: PXD006928 | Pride | 2018-07-11

REPOSITORIES: Pride

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Architectural Features of Human Mitochondrial Cysteine Desulfurase Complexes from Crosslinking Mass Spectrometry and Small-Angle X-Ray Scattering.

Cai Kai K Frederick Ronnie O RO Dashti Hesam H Markley John L JL

Structure (London, England : 1993) 20180705 8

Cysteine desulfurase plays a central role in mitochondrial iron-sulfur cluster biogenesis by generating sulfur through the conversion of L-cysteine to L-alanine and by serving as the platform for assembling other components of the biosynthetic machinery, including ISCU, frataxin, and ferredoxin. The human mitochondrial cysteine desulfurase complex consists of two copies each of NFS1, ISD11, and acyl carrier protein. We describe results from chemical crosslinking coupled with tandem mass spectrom ...[more]

PMID: 29983374

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Human Mitochondria NFS1-ISCU-FXN XL-MS

Project description:Frataxin (FXN) is involved in mitochondrial iron-sulfur (Fe-S) cluster biogenesis and serves to accelerate Fe-S cluster formation. FXN deficiency is associated with Friedreich ataxia, a neurodegenerative disease. Using chemical cross-linking (XL) accompanied with LC-MS/MS, we studied the the interaction between the core complexes Acp-ISD11-NFS1 (AIN) and AIN-ISCU (AINU) with FXN.

2018-07-11 | PXD006938 | Pride

Human mitochondrial cysteine desulfurase complex data set 2

Project description:Cysteine desulfurase plays central role in mitochondrial iron-sulfur cluster biogenesis not only by providing sulfur through the catalysis of L-cysteine to L-alanine but also by serving as the platform for the assembly of other components of the biosynthetic machinery, including ISCU, frataxin, and ferredoxin. Human mitochondrial cysteine desulfurase complex consists of a homodimer with three components: NFS1, ISD11 and acyl carrier protein (ACP). In this study we used chemical crosslinking coupled with tandem mass spectrometry (XC-MS) to investigate the structures of cysteine desulfurase complexes.

2022-03-25 | PXD009128 | Pride

Human mitochondrial cysteine desulfurase complex

2018-07-11 | PXD009079 | Pride

Gene expression in human healthy control and ISCU myopathy patient muscle biopsies

Project description:We performed microarray analysis on ISCU myopathy patient muscle biopsies to identify transcriptional modulation of pathways involved in the cellular response to Fe-S cluster deficiency. We included RNA samples from five healthy control individuals as well as three different ISCU myopathy patients.

2013-09-23 | E-GEOD-48574 | biostudies-arrayexpress

Gene expression in human healthy control and ISCU myopathy patient muscle biopsies

2013-09-23 | GSE48574 | GEO

Overlapping binding site for ferredoxin and frataxin on yeast cysteine desulfurase participating in FeS cluster biogenesis

Project description:In mitochondria cysteine desulfurase (Nfs1) plays a central role in the biosynthesis of iron-sulfur (FeS) clusters, cofactors critical for activity of many cellular proteins. Nfs1 functions both as a sulfur donor for cluster assembly and as a binding platform for other proteins functioning in the process. These include, not only the dedicated scaffold protein (Isu1) on which FeS clusters are synthesized, but also frataxin (Yfh1) and ferredoxin (Yah1). Yfh1 activates cysteine desulfurase enzymatic activity, while Yah1 supplies electrons for persulfide reduction. Yfh1 interaction with Nfs1 is well understood; that of Yah1 is not. Here, based on the results of biochemical experiments involving purified wild-type and variant proteins, we report that in Saccharomyces cerevisiae Yah1 and Yfh1 share an evolutionary conserved interaction site on Nfs1. Consistent with this notion each can displace the other from Nfs1, but are inefficient competitors when a variant with an altered interaction site is used. Thus, the binding mode of Yah1 and Yfh1 interacting with Nfs1 in mitochondria of S. cerevisiae resembles the mutually exclusive binding of ferredoxin and frataxin with cysteine desulfurase reported for the bacterial FeS cluster assembly system. Our findings are consistent with the generally accepted scenario that the mitochondrial FeS cluster assembly system was inherited from bacterial ancestors of mitochondria.

2022-04-04 | PXD029519 | Pride

METTL17 is an Fe-S cluster checkpoint for mitochondrial translation

Project description:Friedreich’s ataxia (FA) is the most common monogenic mitochondrial disease. FA is caused by a depletion of the mitochondrial protein frataxin (FXN), an iron-sulfur (Fe-S) cluster biogenesis factor. To better understand the cellular consequences of FA, we performed quantitative proteome profiling of human cells depleted for FXN. Nearly every known Fe-S cluster-containing protein was depleted in the absence of FXN, indicating that as a rule, cluster binding confers stability to Fe-S proteins. Proteomic and genetic interaction mapping identified impaired mitochondrial translation downstream of FXN loss, and specifically highlighted the methyltransferase-like protein METTL17 as a candidate effector. Using comparative sequence analysis, mutagenesis, biochemistry and cryogenic electron microscopy we show that METTL17 binds to the mitoribosomal small subunit during late assembly and harbors a previously unrecognized [Fe4S4]2+ cluster required for its stability on the mitoribosome. Notably, METTL17 overexpression rescued the mitochondrial translation and bioenergetic defects, but not the cellular growth, of FXN depleted cells. Our data suggest that METTL17 serves as an Fe-S cluster checkpoint: promoting the translation and assembly of Fe-S cluster rich OXPHOS proteins only when Fe-S cluster levels are replete.

2023-12-27 | PXD045443 | Pride

Genetic interaction screen for FXN in K562 cells, to identify genes that are synthetic sick/buffering in the absence of robust Fe-S cluster synthesis

2023-12-18 | GSE242192 | GEO

A complimentary benzophenone cross-linking/mass spectrometry photochemistry

Project description:We introduce a complimentary, heterobifunctional, photoactivatable, benzophenone containing cross-linker and show its successful application to cross-linking/mass spectrometry, by increasing data density, when used alongside a previously developed diazirine-based heterobifunctional cross-linker.

2017-04-26 | PXD004920 | Pride

Cross-linking/mass spectrometry for the 13th Community Wide Experiment on the Critical Assessment of Techniques for Protein Structure Prediction (CASP13)

Project description:High-density cross-linking/mass spectrometry data was provided for four targets (T0957, T0968, T0975 and T0987) in the CASP13 experiment (https://www.predictioncenter.org/casp13/index.cgi).

2019-10-07 | PXD010884 | Pride

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