Annotation inferences using phylogenetic trees
Automatic assignment of GO terms using logical inference, based on on inter-ontology links
Combined Automated Annotation using Multiple IEA Methods
The subunit composition of the human NADH dehydrogenase obtained by rapid one-step immunopurification.
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Immunocapture of human Complex I followed by 1D/2D gel electrophoresis, MALDI-TOF peptide mass fingerprinting and nanoflow LC-MS/MS resolved 42 polypeptides, matching the subunit inventory of the better-characterized bovine complex; NDUFA6 is among them.
"homologues of 42 polypeptides detected so far in the more extensively studied"
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The concordance between human and bovine Complex I isolated by different procedures gives confidence that the identified polypeptides really are constituents of the complex rather than co-purifying contaminants.
"The concordance of data from human and bovine complex I isolated by different"
Identification of mitochondrial complex I assembly intermediates by tracing tagged NDUFS3 demonstrates the entry point of mitochondrial subunits.
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An inducible NDUFS3-GFP system in HEK293 cells resolved six distinct NDUFS3-GFP-containing subcomplexes on blue-native blots, also seen in wild-type mitochondria, giving direct evidence that Complex I assembles stepwise.
"NDUFS3-GFP-containing subcomplexes gradually appeared on a blue native Western"
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Differential solubilization and heat incubation distinguished genuine assembly intermediates from breakdown products, so the composition analysis that places NDUFA6 in the complex is reporting assembly rather than instability.
"demonstrated by differential solubilization and heat incubation, which"
Accessory subunits are integral for assembly and function of human mitochondrial complex I.
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Human complex I comprises 45 subunits, of which only 14 core subunits are shared with bacteria and essential for enzymatic function; the role of the remaining 31 accessory subunits, NDUFA6 among them, was previously unclear.
"mitochondrial respiratory chain and is composed of 45 subunits in humans, making"
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Knockout cell lines were generated by gene editing for every accessory subunit and profiled by quantitative proteomics; 25 accessory subunits proved strictly required for assembly of a functional complex.
"Here we use gene editing to generate human knockout"
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Loss of any given subunit destabilized the other subunits of the same structural module - the observation that assigns each accessory subunit, including NDUFA6, to a module of the complex.
"of each subunit affects the stability of other subunits residing in the same"
Architecture of Human Mitochondrial Respiratory Megacomplex I(2)III(2)IV(2).
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Cryo-EM of the human respiratory megacomplex I2III2IV2 resolved 140 subunits together with associated cofactors, providing the structural context in which individual Complex I subunits were placed.
"chain megacomplex-I2III2IV2 (MCI2III2IV2) with 140 subunits and a subset of"
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The structure gives a precise individual assignment of the subunits of human Complex I, the basis for the ComplexPortal IDA/IPI annotations placing NDUFA6 in Complex I in the inner membrane.
"The structure not only reveals the precise assignment of individual subunits of"
Assembly of mammalian oxidative phosphorylation complexes I-V and supercomplexes.
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In the OXPHOS complexes the catalytic work is done by a set of core proteins, while the numerous supernumerary subunits - the class NDUFA6 belongs to - serve assembly, regulation and stability roles.
"supernumerary' subunits that play essential roles in assembly, regulation"
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Complexes I, III and IV associate into respiratory supercomplexes or respirasomes, the higher-order context in which Complex I subunits such as NDUFA6 operate.
"established that complexes I, III and IV interact with each other, forming the"
Bi-allelic Mutations in NDUFA6 Establish Its Role in Early-Onset Isolated Mitochondrial Complex I Deficiency.
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Next-generation sequencing of four unrelated children with suspected mitochondrial disease identified bi-allelic variants in NDUFA6, which encodes a 15 kDa LYR-motif-containing Complex I subunit forming part of the Q-module.
"identified bi-allelic variants in NDUFA6, encoding a 15 kDa LYR-motif-containing"
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Complexome profiling of subjects' fibroblasts showed a marked reduction of incorporated NDUFA6 together with a concomitant reduction of the other Q-module subunits NDUFAB1, NDUFA7 and NDUFA12 - the structural evidence that NDUFA6 holds the Q-module together.
"concomitant reduction in other Q-module subunits, including NDUFAB1, NDUFA7, and"
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Lentiviral transduction of the subjects' fibroblasts normalized Complex I, establishing that the assembly defect is attributable to loss of NDUFA6 rather than to linkage or genetic background.
"Lentiviral transduction of subjects' fibroblasts showed normalization"
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The residual ~830 kDa Complex I intermediate (P- and Q-modules, lacking the N-module) was found in complex with assembled Complex III and IV holoenzymes, supporting supercomplex formation independent of a complete Complex I.
"complex with assembled complex III and IV holoenzymes despite lacking the"
Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
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More than 8,000 proteins were classified in mitochondrial preparations of human cells to define MitoCoP, a high-confidence mitochondrial proteome of over 1,100 proteins; NDUFA6's membership supports its mitochondrial localization.
"mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP)"
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The dataset is quantitative and spans six orders of magnitude of abundance, but it is an organelle-level inventory that does not resolve submitochondrial compartment, so it cannot support the inner-membrane term.
"The abundance of MitoCoP proteins covers six orders of"
In situ hybridisation mapping of genomic clones for five human respiratory chain complex I genes.
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Human cosmid and P1 libraries were screened with short cDNA probes to isolate genomic clones for five Complex I subunit genes, including cI-B14 (NDUFA6).
"and P1 libraries for components of the complex I multi-subunit enzyme of"
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The study's result is a set of chromosomal assignments obtained by in situ hybridisation - NDUFA6 to 21q22 - and nothing more; no enzymatic activity of any of the five proteins was assayed, so it cannot support an `enables` claim for GO:0008137.
"situ hybridisation studies we determined the following chromosome locations:"
cDNA of eight nuclear encoded subunits of NADH:ubiquinone oxidoreductase: human complex I cDNA characterization completed.
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Complex I is located in the inner mitochondrial membrane and its main function is the transport of electrons from NADH to ubiquinone, accompanied by translocation of protons from the matrix to the intermembrane space.
"function is the transport of electrons from NADH to ubiquinone, which is"
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The paper reports cDNA sequences for the eight remaining uncharacterized nuclear-encoded subunits, completing the inventory of the 41 then-known human Complex I proteins; it is a sequence-characterization study and assays no enzymatic activity.
"Here we report the cDNA sequences of the hitherto"
Complex I oxidises NADH to NAD+, reduces CoQ to CoQH2
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Reactome describes Complex I as an L-shaped 45-subunit enzyme whose IP and FP fractions protrude into the matrix while the HP arm lies within the inner mitochondrial membrane, with FMN and eight Fe-S clusters carrying electrons from NADH to ubiquinone - the catalytic machinery NDUFA6 does not possess.
"the HP arm lying within the inner mitochondrial membrane"
Intermediate 1 binds HP subcomplex to form Intermediate 2
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The hydrophobic protein (HP) fraction is anchored to the inner mitochondrial membrane by the Intermediate 1 assembly factors NDUFAF3, NDUFAF4 and TIMMDC1 to form Intermediate 2.
"anchored to the inner mitochondrial membrane by Intermediate"
Peripheral arm subunits bind the 815kDa complex to form a 980kDa complex
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The peripheral (flavoprotein) arm subunits join the 815 kDa intermediate to form the 980 kDa complex, a late step of the inner-membrane Complex I biogenesis pathway.
"Subunits NDUFA12, NDUFS1, 4, 6, NDUFV1, 2 and 3 with the assembly factor"
Intermediate 2 binds MT-ND1:NDUFAF5:NDUFAF6 to form a 315kDa subcomplex
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The 315 kDa intermediate is centred on the core iron-sulfur subunits NDUFS2 and NDUFS3, and the IP subcomplex is anchored to the inner mitochondrial membrane by MT-ND1 - the Q-module context in which NDUFA6 sits.
"to the inner mitochondrial membrane by NADH-ubiquinone oxidoreductase chain 1"
The MCIA complex, NDUFAF2-7 all dissociate from the 980kDa complex, resulting in Complex I
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In the final step of Complex I biogenesis the MCIA complex and the assembly factors NDUFAF2-7 and TIMMDC1 dissociate from the 980 kDa complex to leave mature Complex I - the distinction between transient assembly factors and true subunits such as NDUFA6.
"The MCIA complex, NDUFAF2-7 all dissociate from the 980kDa complex"
ND4, ND5 bind the 550kDa complex to form the 815kDa complex
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The distal membrane-arm subunits MT-ND4 and MT-ND5 associate with the 550 kDa complex to form the 815 kDa complex, requiring DMAC1 and DMAC2.
"Distal components of the membrane arm MT-ND4 and 5 associate with the 550kDa"
The 315kDa subcomplex binds the 370kDa subcomplex to form the 550kDa complex
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The 315 kDa and 370 kDa subcomplexes associate to form the 550 kDa complex, an intermediate step of the inner-membrane Complex I biogenesis pathway.
"The 315kDa and 370kDa subcomplexes associate to form a 550kDa complex"