NDUFAF7 Methylates Arginine 85 in the NDUFS2 Subunit of Human Complex I

Rhein, Virginie; Carroll, Joe; Ding, Shuzhe; Fearnley, Ian M.; Walker, John E.

doi:10.1074/jbc.m113.518803

Cited by 94 publications

(117 citation statements)

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“…How these assembly factors function is not known, but they may stabilize the subcomplexes and help to join them to other subcomplexes to build the complete enzyme. Two additional proteins involved in the assembly of complex I, C20orf7 (NDUFAF5) and MidA (NDUFAF7), are predicted to be protein methyltransferases and NDUFAF7 methylates subunit NDUFS2 (39,40). Ind1 is involved in the assembly of iron-sulfur clusters in complex I and C8orf38 (NDUFAF6) stabilizes subunit MT-ND1 (41, 42).…”

Section: Discussionmentioning

confidence: 99%

Assembly factors for the membrane arm of human complex I

Andrews

Carroll

Ding

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Mitochondrial respiratory complex I is a product of both the nuclear and mitochondrial genomes. The integration of seven subunits encoded in mitochondrial DNA into the inner membrane, their association with 14 nuclear-encoded membrane subunits, the construction of the extrinsic arm from 23 additional nuclear-encoded proteins, iron-sulfur clusters, and flavin mononucleotide cofactor require the participation of assembly factors. Some are intrinsic to the complex, whereas others participate transiently. The suppression of the expression of the NDUFA11 subunit of complex I disrupted the assembly of the complex, and subcomplexes with masses of 550 and 815 kDa accumulated. Eight of the known extrinsic assembly factors plus a hydrophobic protein, C3orf1, were associated with the subcomplexes. The characteristics of C3orf1, of another assembly factor, TMEM126B, and of NDUFA11 suggest that they all participate in constructing the membrane arm of complex I. mitochondria | respiratory chain | NADH:ubiquinone oxidoreductase

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Section: Discussionmentioning

confidence: 99%

Assembly factors for the membrane arm of human complex I

Andrews

Carroll

Ding

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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132

125

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“…These cytoplasmic and nuclear enzymes have been shown to complement protein lysine methyltransferases and indeed perhaps even protein kinases in modulating transcriptional activation/repression and controlling mRNA splicing, DNA repair, the cell cycle, and signaling pathways (13,15,40,82). A mitochondrial seven-beta strand methyltransferase from an unrelated family, designed NDUFAD7, modifies a subunit of complex I in the mammalian electron transport chain (83,84). All of these enzymes modify only the terminal ω-nitrogen atoms of the arginine residue.…”

Section: An Unusual Protein Arginine Methyltransferase That Modifiesmentioning

confidence: 99%

The ribosome: A hot spot for the identification of new types of protein methyltransferases

Clarke¹

2018

Journal of Biological Chemistry

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Cellular physiology depends on the alteration of protein structures by covalent modification reactions. Using a combination of bioinformatic, genetic, biochemical, and mass spectrometric approaches, it has been possible to probe ribosomal proteins from the yeast Saccharomyces cerevisiae for posttranslationally methylated amino acid residues and for the enzymes that catalyze these modifications. These efforts have resulted in the identification and characterization of the first protein histidine methyltransferase, the first N-terminal protein methyltransferase, two unusual types of protein arginine methyltransferases, and a new type of cysteine methylation. Two of these enzymes may modify their substrates during ribosomal assembly because the final methylated histidine and arginine residues are buried deep within the ribosome with contacts only with RNA. Two of these modifications occur broadly in eukaryotes, including humans, while the others demonstrate a more limited phylogenetic range. Analysis of strains where the methyltransferase genes are deleted has given insight into the physiological roles of these modifications. These reactions described here add diversity to the modifications that generate the typical methylated lysine and arginine residues previously described in histones and other proteins. Regulation of biological function by protein methylation reactionsIt is more and more apparent just how much of biological function is dependent upon posttranslational modifications (1). The human genome encodes some 900 enzymes catalyzing just protein phosphorylation or ubiquitination (2,3). However, it is now clear that methyl groups can stand beside phosphate groups and ubiquitin as major players in controlling the physiological functions of proteins. We are beginning to understand how the much greater diversity of protein methylation reactions can give rise to a greater diversity of function (1,4-8). We are also learning the importance of crosstalk between protein and DNA methylation reactions (9) and among protein methylation, phosphorylation, acetylation, and ubiquitination reactions (10-12). Finally, we are discovering how alterations in protein methylation pathways can lead to human pathology, particularly in cancer (13-15).The collection of over sixty human protein arginine and lysine methyltransferases that leave histone "marks" recognized by reader proteins to guide gene expression are perhaps the poster children for the importance of protein methyltransferases (16-17). However, recent work has emphasized the importance of methylating non-histone substrates at these residues, particularly ribosomal proteins, translation factors, and transcription factors in a wide variety of organisms (7,8,15,18,19). Furthermore, the methylation of lysine and arginine residues represents just the tip of the iceberg in protein methylation -modifications have also been established at histidine, modified histidine (diphthamide), glutamate, glutamine, asparagine, Lisoaspartate, D-aspartate, cysteine, isoprenylcysteine, me...

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“…29,30 Although these four mutations have been found to be related to other diseases and no evidences so far indicates that they are involved in myopia according to their function, we still could not exclude their contribution to myopia develompent in such a small pedigree. Whereas in the case of NDUFAF7, as a mitochondrial assembly factor, it is involved in mitochondrial respiratory chain system, 31 and previous research showed that the decline in ATP synthesis via mitochondrial energy metabolism leads to severe visual impairment. 32 Thus, we decided to focus on the function investigation of the mutant (MT) NDUFAF7 detected as a de novo missense mutation (p.D266E) in this family.…”

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confidence: 99%

A Novel Potentially Causative Variant of NDUFAF7 Revealed by Mutation Screening in a Chinese Family With Pathologic Myopia

Wang

Liu

Chen

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Pathologic myopia described as myopia accompanied by severe deformation of the eye besides excessive elongation of eye, is usually a genetic heterogeneous disorder characterized by extreme, familial, early-onset vision loss. However, the exact pathogenesis of pathologic myopia remains unclear. In this study, we screened a Han Chinese family with pathologic myopia to identify the causative mutation and explore the possible pathogenic mechanism based on evaluation of the biological functions of the mutation. METHODS.We identified the mutations in a family with pathologic myopia by single nucleotide polymorphism array combined with short tandem repeat microsatellite marker analysis and exome sequencing. Mutations were validated among family members by direct Sanger sequencing. The subcellular localization of the protein variant was investigated by immunofluorescence, and the stability of the mutant protein was determined by immunoblotting. Intracellular levels of adenosine triphosphate and reactive oxygen species and complex I activity were measured by traditional biochemical methods to determine the functional role of the disease-associated mutation.RESULTS. The novel missense mutation: c.798C>G (p.Asp266Glu) in NDUFAF7, cosegregated with the disease and the resulting amino acid substitution affected a highly conserved residue in its protein. The mutation D266E in NDUFAF7 impaired complex I activity, which resulted in decreased ATP levels in cultured cells. CONCLUSIONS.We propose that the heterozygous mutation (c.798C>G) in NDUFAF7 may contribute to the pathogenesis of pathologic myopia, possibly by interfering with the phototransduction cascade. Mitochondrial dysfunction during eye development may lead to pathologic myopia.Keywords: pathologic myopia, NDUFAF7, causative mutation H igh myopia is an extreme form of myopia, usually defined by an ocular axial length >26 mm or a refractive error < À6.00 diopters (D). High myopia is a leading cause of blindness worldwide, with a relatively high prevalence of 1% to 5% in Asian countries, and as high as 4.1% in China. [1][2][3][4] High myopia can be complicated by pathology in 8% of high myopia in that there might be other genetic variants that play a role in this process compared to high myopia without pathology.5-8 Pathologic myopia (PM) generally causes irreversible visual impairment, which involves not only elongation of the eye, but also characteristic pathologic changes in the retina, choroid, and sclera, such as posterior sclera staphyloma, macular degeneration, lacquer cracks, and chorioretinal atrophy.9 Pathologic myopia is highly heritable, and genetic linkage studies have identified over 20 loci for PM, with autosomal dominant, autosomal recessive, or X-linked recessive modes of inheritance. [10][11][12][13] More than 70 genes related to refractive variation have been screened out by association studies. 14 Furthermore, recent studies have indicated that environment is another factor influencing the growth of the eye.15 Environmental factors, such as ...

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NDUFAF7 Methylates Arginine 85 in the NDUFS2 Subunit of Human Complex I

Cited by 94 publications

References 83 publications

Assembly factors for the membrane arm of human complex I

Assembly factors for the membrane arm of human complex I

The ribosome: A hot spot for the identification of new types of protein methyltransferases

A Novel Potentially Causative Variant of NDUFAF7 Revealed by Mutation Screening in a Chinese Family With Pathologic Myopia

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