Mmf1p, a Novel Yeast Mitochondrial Protein Conserved throughout Evolution and Involved in Maintenance of the Mitochondrial Genome

Oxelmark, Ellinor; Marchini, Antonio; Malanchi, Ilaria; Magherini, Francesca; Jaquet, Laurence; Hajibagheri, M. A.; Blight, Ken; Jauniaux, J. C.; Tommasino, Massimo

doi:10.1128/mcb.20.20.7784-7797.2000

Cited by 57 publications

(84 citation statements)

References 29 publications

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“…First, the inhibition was titratable and declined with decreasing protein concentration. Second, the data suggested that YjgF had a catalytic role in the assay because 1 M protein reduced PRA formation by ϳ300 M. Significantly, the human homolog (UK114) was active in this assay, consistent with the finding that UK114 complemented the yjgF mutant phenotypes in S. enterica 4 and Saccharomyces cerevisiae (34) in vivo. Together, these results emphasized that this protein family is characterized both by high sequence identity and functional conservation.…”

Section: Discussionsupporting

confidence: 74%

Members of the YjgF/YER057c/UK114 Family of Proteins Inhibit Phosphoribosylamine Synthesis in Vitro

Lambrecht¹,

Browne

Downs

2010

Journal of Biological Chemistry

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The YjgF/YER057c/UK114 family of proteins is highly conserved across all three domains of life and currently lacks a consensus biochemical function. Analysis of Salmonella enterica strains lacking yjgF has led to a working model in which YjgF functions to remove potentially toxic secondary products of cellular enzymes. Strains lacking yjgF synthesize the thiamine precursor phosphoribosylamine (PRA) by a TrpD-dependent mechanism that is not present in wild-type strains. Here, PRA synthesis was reconstituted in vitro with anthranilate phosphoribosyltransferase (TrpD), threonine dehydratase (IlvA), threonine, and phosphoribosyl pyrophosphate. TrpD-dependent PRA formation in vitro was inhibited by S. enterica YjgF and the human homolog UK114. Thus, the work herein describes the first biochemical assay for diverse members of the highly conserved YjgF/YER057c/UK114 family of proteins and provides a means to dissect the cellular functions of these proteins.

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Section: Discussionsupporting

confidence: 74%

Members of the YjgF/YER057c/UK114 Family of Proteins Inhibit Phosphoribosylamine Synthesis in Vitro

Lambrecht¹,

Browne

Downs

2010

Journal of Biological Chemistry

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“…In particular, we observed the depletion of two proteins, MMF1 and Ilv5p (Fig. 2), which are necessary for mitochondrial DNA stability and mitochondrial functionality (32,33). A recent transcriptome analysis of cdc48 S565G cells demonstrated nuclear genes coding for mitochondrial proteins to be the largest group of differentially regulated genes (45).…”

Section: Mitochondria Are Crucially Impaired In Apoptotic Cdc48mentioning

confidence: 98%

“…2B, panel 1) and ketol acid reductoisomerase (Ilv5p, Table 1), two mitochondrial proteins fundamental for the stability of mitochondrial DNA (32,33), suggest reduced mitochondrial functionality upon CDC48 mutation. We found depletion of mitochondrial cyclophilin C (Fig.…”

Section: Mitochondria In Cdc48 S565g Cells Are Enlarged Compared Withmentioning

confidence: 99%

Crucial Mitochondrial Impairment upon CDC48 Mutation in Apoptotic Yeast

Braun¹,

Zischka

Madeo

et al. 2006

Journal of Biological Chemistry

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Mutation in CDC48 (cdc48 S565G ), a gene essential in the endoplasmic reticulum (ER)-associated protein degradation (ERAD) pathway, led to the discovery of apoptosis as a mechanism of cell death in the unicellular organism Saccharomyces cerevisiae. Elucidating Cdc48p-mediated apoptosis in yeast is of particular interest, because Cdc48p is the highly conserved yeast orthologue of human valosin-containing protein (VCP), a pathological effector for polyglutamine disorders and myopathies. Here we show distinct proteomic alterations in mitochondria in the cdc48 S565G yeast strain. These observed molecular alterations can be related to functional impairment of these organelles as suggested by respiratory deficiency of cdc48 S565G cells. Mitochondrial dysfunction in the cdc48 S565G strain is accompanied by structural damage of mitochondria indicated by the accumulation of cytochrome c in the cytosol and mitochondrial enlargement. We demonstrate accumulation of reactive oxygen species produced predominantly by the cytochrome bc 1 complex of the mitochondrial respiratory chain as suggested by the use of inhibitors of this complex. Concomitantly, emergence of caspase-like enzymatic activity occurs suggesting a role for caspases in the cell death process. These data strongly point for the first time to a mitochondrial involvement in Cdc48p/VCPdependent apoptosis.Fundamental cellular processes, such as the formation of organelles (ER,3 Golgi apparatus, and the nuclear envelope), or ubiquitin-dependent ER-associated protein degradation (ERAD) have been linked to the yeast protein Cdc48p and its highly conserved mammalian orthologue VCP (1-4). Mutations in VCP have been associated with "inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia" (IBMPFD), a dominant human disorder (5, 6). A genetic screening of a Drosophila model for human polyglutamine diseases, a class of inherited neurodegenerative disorders, identified the Drosophila homologue of Cdc48p/VCP as a modulator of apoptotic cell death (7), leading these authors to propose VCP as a pathological effector for polyglutamine-induced neurodegeneration. However, the cellular mechanisms underlying VCP-mediated cell death in these human disorders remain largely unknown. Apoptotic phenotypes in cells expressing mutated Cdc48p/ VCP have originally been described in budding yeast (8) and were thereafter confirmed in mammalian cell cultures (9, 10), in trypanosomes (11), and in zebrafish (12). Notably, Cdc48p was the first apoptotic mediator found in Saccharomyces cerevisiae (8). The expression of a point-mutated CDC48 gene (cdc48 S565G ) leads to a characteristic apoptotic phenotype: phosphatidylserine externalization, DNA fragmentation, chromatin condensation, nuclear fragmentation, and vacuolization (8, 13). These results obtained in the cdc48 S565G strain initiated the establishment of yeast as a model to study evolutionary conserved mechanisms of apoptotic regulation (14 -16).Mitochondria play a crucial role in many apoptotic pathways in ...

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“…Members of this protein family share extensive similarities and have been implicated in diverse cellular processes in a number of organisms (17,24,28,39,40,46,47,50,67). Though no in vitro activity has been described, in the annotation of various genomes more than 10 different functions have been attributed to members of this family (http://e2f.umbi.umd .edu).…”

mentioning

confidence: 99%

Reduced Transaminase B (IlvE) Activity Caused by the Lack ofyjgFIs Dependent on the Status of Threonine Deaminase (IlvA) inSalmonella entericaSerovar Typhimurium

2004

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The YjgF/YER057c/UK114 family is a highly conserved class of proteins that is represented in the three domains of life. Thus far, a biochemical function demonstrated for these proteins in vivo or in vitro has yet to be defined. In several organisms, strains lacking a YjgF homolog have a defect in branched-chain amino acid biosynthesis. This study probes the connection between yjgF and isoleucine biosynthesis in Salmonella enterica. In strains lacking yjgF the specific activity of transaminase B, catalyzing the last step in the synthesis of isoleucine, was reduced. In the absence of yjgF, transaminase B activity could be restored by inhibiting threonine deaminase, the first enzymatic step in isoleucine biosynthesis. Strains lacking yjgF showed an increased sensitivity to sulfometruron methyl, a potent inhibitor of acetolactate synthase. Based on work described here and structural reports in the literature, we suggest a working model in which YjgF has a role in protecting the cell from toxic effects of imbalanced ketoacid pools.

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Mmf1p, a Novel Yeast Mitochondrial Protein Conserved throughout Evolution and Involved in Maintenance of the Mitochondrial Genome

Cited by 57 publications

References 29 publications

Members of the YjgF/YER057c/UK114 Family of Proteins Inhibit Phosphoribosylamine Synthesis in Vitro

Members of the YjgF/YER057c/UK114 Family of Proteins Inhibit Phosphoribosylamine Synthesis in Vitro

Crucial Mitochondrial Impairment upon CDC48 Mutation in Apoptotic Yeast

Reduced Transaminase B (IlvE) Activity Caused by the Lack ofyjgFIs Dependent on the Status of Threonine Deaminase (IlvA) inSalmonella entericaSerovar Typhimurium

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