NUBPL
| NUBPL | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | NUBPL, C14orf127, IND1, huInd1, nucleotide binding protein like, MC1DN21, NUBP iron-sulfur cluster assembly factor, mitochondrial | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 613621; MGI: 1924076; HomoloGene: 11854; GeneCards: NUBPL; OMA:NUBPL - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Iron-sulfur protein NUBPL (IND1) also known as nucleotide-binding protein-like (NUBPL), IND1 homolog, Nucleotide-binding protein-like or huInd1 is an iron-sulfur (Fe/S) protein that, in humans, is encoded by the NUBPL gene, located on chromosome 14q12. It has an early role in the assembly of the mitochondrial complex I assembly pathway.[5][6]
Structure
NUBPL is located on the q arm of chromosome 14 in position 12 and has 18 exons.[5] The NUBPL gene produces a 5.9 kDa protein composed of 54 amino acids.[7][8] The structure of the protein includes a presumed iron-sulfur binding (CxxC) signature, a nucleotide-binding domain which has been highly conserved, and a mitochondrial targeting sequence in the N-terminal.[9] NUBPL is required for the assembly of complex I, which is composed of 45 evolutionally conserved core subunits, including both mitochondrial DNA and nuclear encoded subunits. One of its arms is embedded in the inner membrane of the mitochondria, and the other is embedded in the organelle. The two arms are arranged in an L-shaped configuration. The total molecular weight of the complex is 1MDa.[10]
Function
The NUBPL gene encodes a protein that is a member of the Mrp/NBP35 ATP-binding family. This protein is required for the assembly of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), the first oligomeric enzymatic complex of the mitochondrial respiratory chain located in the inner mitochondrial membrane.[6][5] Its role in assembly is the delivery of one or more iron–sulfur (Fe-S) clusters to complex I subunits in anaerobic conditions in vitro.[6][9] The dysfunction of NUBPL results in an irregular assembly of the peripheral arm of complex I, which may lead to a decrease in activity. Knockdown of the protein also causes abnormal mitochondrial ultrastructure characterized by respiratory supercomplex remodeling, christa membrane loss, and abnormally high lactate levels.[11][9]
Discovery
Sheftel, et al. (2009) used RNA interference (RNAi) to delete the NUBPL gene in yeast (Y. lipolytica). They observed decreased levels and activity of mitochondrial complex I, leading them to conclude that NUBPL is required for complex I assembly and activity. Their experiments showed functional conservation of NUBPL in yeast and humans, an indication that the protein serves an important function. Sheftel, et al. observed structural abnormalities in mitochondria that were NUBPL-depleted mitochondria.[9]
Clinical significance
The absence of NUBPL disrupts the early stage of the mitochondrial complex I assembly pathway. NUBPL-depleted cells were observed to have an abnormal sub complex of proteins normally found in the membrane arm of complex I. A decrease in the presence of complex I subunit proteins, NDUFS1, NDUFV1, NDUFS3, and NDUFA13 indicated a failure of normal complex I assembly.[9] Mitochondrial complex I deficiency involving the dysfunction of the mitochondrial respiratory chain may cause a wide range of clinical manifestations from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease.[6]
High-throughput DNA sequencing was used to identify variants in 103 candidate genes in 103 patients with mitochondrial complex 1 disorders. Heterozygous variants in the NUBPL were identified in one patient. cDNA complementation studies showed that the variants can cause complex 1 deficiency. The finding in this patient is consistent with autosomal recessive inheritance NUBPL-associated complex I deficiency, and supports the pathogenicity of the variants that were identified.[11] Complex compound heterozygous variants were identified in the NUBPL gene in this patient.[11] In exon 2, a paternally-inherited G>A point mutation (c.166 G>A) resulting in missense substitution of gly56-to-arg (G56R) was observed. Two variants were maternally-inherited: T>C point mutation (c.815-27 T>C) that caused a splicing error and a complex deletion of exons 1-4 and duplication involving exon 7. Two of 232 (1%) control chromosomes were found to have the c.166 G>A pathogenic variant. This individual identified was noted to have motor delays and developmental delay at 2 years of age.[11] He never achieved independent walking. He developed myopathy, nystagmus, ataxia, upper motor neuron signs, and absence seizures. Brain MRI showed leukodystrophy with involvement of the cerebellar cortex and deep white matter. At age 8, he had spasticity, ataxia, and speech problems.
Several patients from with early MRI abnormalities of the cerebellum, deep cerebral white matter and corpus callosum. In this small sample, it was noted that later imaging studies showed improvements to the corpus callosum and cerebral white matter abnormalities, while the cerebellar abnormalities worsen and brainstem abnormalities arise. Using whole exome sequencing, four of the patients had a mitochondrial complex І deficiency identified using other laboratory methods. All four of the patients had compound pathogenic variants in the NUBPL gene.[12]
Interactions
NUBPL has protein-protein interactions with DNAJB11, MTUS2, RNF2, and UFD1L.[6]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000151413 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000035142 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b c "Entrez Gene: NUBPL nucleotide binding protein like [ Homo sapiens (human) ]". Retrieved 2018-07-27.
- ^ a b c d e "NUBPL - Iron-sulfur protein NUBPL - Homo sapiens (Human) - NUBPL gene & protein". www.uniprot.org. Retrieved 2018-07-27.
- ^ Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, et al. (October 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338.
- ^ Yao, Daniel. "Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) —— Protein Information". amino.heartproteome.org. Archived from the original on 2018-07-28. Retrieved 2018-07-27.
- ^ a b c d e Sheftel AD, Stehling O, Pierik AJ, Netz DJ, Kerscher S, Elsässer HP, Wittig I, Balk J, Brandt U, Lill R (November 2009). "Human ind1, an iron-sulfur cluster assembly factor for respiratory complex I". Molecular and Cellular Biology. 29 (22): 6059–73. doi:10.1128/mcb.00817-09. PMC 2772561. PMID 19752196.
- ^ Rhein VF, Carroll J, Ding S, Fearnley IM, Walker JE (July 2016). "NDUFAF5 Hydroxylates NDUFS7 at an Early Stage in the Assembly of Human Complex I". The Journal of Biological Chemistry. 291 (28): 14851–60. doi:10.1074/jbc.M116.734970. PMC 4938201. PMID 27226634.
- ^ a b c d Calvo SE, Tucker EJ, Compton AG, Kirby DM, Crawford G, Burtt NP, et al. (October 2010). "High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency". Nature Genetics. 42 (10): 851–8. doi:10.1038/ng.659. PMC 2977978. PMID 20818383.
- ^ Kevelam SH, Rodenburg RJ, Wolf NI, Ferreira P, Lunsing RJ, Nijtmans LG, et al. (April 2013). "NUBPL mutations in patients with complex I deficiency and a distinct MRI pattern". Neurology. 80 (17): 1577–83. doi:10.1212/wnl.0b013e31828f1914. PMC 3662327. PMID 23553477.