Biology:NDUFS4

From HandWiki
Revision as of 06:38, 10 February 2024 by MedAI (talk | contribs) (correction)
(diff) ← Older revision | Latest revision (diff) | Newer revision → (diff)
Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial (NDUFS4) also known as NADH-ubiquinone oxidoreductase 18 kDa subunit is an enzyme that in humans is encoded by the NDUFS4 gene.[1][2] This gene encodes a nuclear-encoded accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I, or NADH:ubiquinone oxidoreductase). Complex I removes electrons from NADH and passes them to the electron acceptor ubiquinone. Mutations in this gene can cause mitochondrial complex I deficiencies such as Leigh syndrome.[3]

Structure

NDUFS4 is located on the q arm of chromosome 5 in position 11.2 and has 8 exons.[4] The NDUFS4 gene produces a 20.1 kDa protein composed of 175 amino acids.[5][6] NDUFS4, the protein encoded by this gene, is a member of the complex I NDUFS4 subunit family. It is a peripheral membrane protein located on the matrix side of the inner mitochondrial membrane. NDUFS4 is a component of the iron-sulfur (IP) fragment of the enzyme and contains a transit peptide domain, 4 turns, 6 beta strands, and 4 alpha helixes.[7][8] Alternative splicing results in multiple transcript variants.[3]

Function

Complex I, or NADH:ubiquinone oxidoreductase, the first multisubunit enzyme complex of the mitochondrial respiratory chain, plays a vital role in cellular ATP production, the primary source of energy for many crucial processes in living cells. It removes electrons from NADH and passes them by a series of different protein-coupled redox centers to the electron acceptor ubiquinone. In well-coupled mitochondria, the electron flux leads to ATP generation via the building of a proton gradient across the inner membrane. Complex I is composed of at least 41 subunits, of which 7 are encoded by the mitochondrial genome (ND1-6, ND4L) and the remainder by nuclear genes.[1][3]

Clinical significance

Mutations in the NDUFS4 gene are associated with Mitochondrial Complex I Deficiency, which is autosomal recessive. This deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders.[9][10] Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype–phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible.[11] However, the majority of cases are caused by mutations in nuclear-encoded genes.[12][13] It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease.[14] Complex I deficiency with autosomal recessive inheritance results from mutation in nuclear-encoded subunit genes, including NDUFV1, NDUFV2, NDUFS1, NDUFS2, NDUFS3, NDUFS6, NDUFS7, NDUFS8, NDUFA2, NDUFA11, NDUFAF3, NDUFAF10, NDUFB3, NDUFB9, ACAD9, FOXRED1, and MTFMT.

Interactions

NDUFS4 has been shown to have 58 binary protein-protein interactions including 57 co-complex interactions. NDUFS4 appears to interact with UBE2G2.[15]

References

  1. ↑ 1.0 1.1 "Demonstration of a new pathogenic mutation in human complex I deficiency: a 5-bp duplication in the nuclear gene encoding the 18-kD (AQDQ) subunit". American Journal of Human Genetics 62 (2): 262–8. February 1998. doi:10.1086/301716. PMID 9463323. 
  2. ↑ "Intron based radiation hybrid mapping of 15 complex I genes of the human electron transport chain". Cytogenetics and Cell Genetics 82 (1–2): 115–9. Nov 1998. doi:10.1159/000015082. PMID 9763677. 
  3. ↑ 3.0 3.1 3.2 "Entrez Gene: NDUFS4 NADH dehydrogenase (ubiquinone) Fe-S protein 4, 18kDa (NADH-coenzyme Q reductase)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4724.  This article incorporates text from this source, which is in the public domain.
  4. ↑ "Entrez Gene: Cytochrome c oxidase assembly factor 7 (putative)". https://www.ncbi.nlm.nih.gov/gene/65260.  This article incorporates text from this source, which is in the public domain.
  5. ↑ Yao, Daniel. "Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) —— Protein Information". https://amino.heartproteome.org/web/protein/O43181. 
  6. ↑ "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research 113 (9): 1043–53. October 2013. doi:10.1161/CIRCRESAHA.113.301151. PMID 23965338. 
  7. ↑ "NDUFS4 - NADH dehydrogenase [ubiquinone iron-sulfur protein 4, mitochondrial precursor - Homo sapiens (Human) - NDUFS4 gene & protein"] (in en). https://www.uniprot.org/uniprot/O43181.  This article incorporates text available under the CC BY 4.0 license.
  8. ↑ "UniProt: the universal protein knowledgebase". Nucleic Acids Research 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMID 27899622. 
  9. ↑ "NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency". The Journal of Clinical Investigation 114 (6): 837–45. September 2004. doi:10.1172/JCI20683. PMID 15372108. 
  10. ↑ "De novo mutations in the mitochondrial ND3 gene as a cause of infantile mitochondrial encephalopathy and complex I deficiency". Annals of Neurology 55 (1): 58–64. January 2004. doi:10.1002/ana.10787. PMID 14705112. 
  11. ↑ "Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing". Journal of Medical Genetics 49 (4): 277–83. April 2012. doi:10.1136/jmedgenet-2012-100846. PMID 22499348. https://epub.ub.uni-muenchen.de/21895/1/oa_21895.pdf. 
  12. ↑ "Isolated complex I deficiency in children: clinical, biochemical and genetic aspects". Human Mutation 15 (2): 123–34. 2000. doi:10.1002/(SICI)1098-1004(200002)15:2<123::AID-HUMU1>3.0.CO;2-P. PMID 10649489. 
  13. ↑ "Respiratory chain complex I deficiency". American Journal of Medical Genetics 106 (1): 37–45. 2001. doi:10.1002/ajmg.1397. PMID 11579423. 
  14. ↑ "Human complex I deficiency: clinical spectrum and involvement of oxygen free radicals in the pathogenicity of the defect". Biochimica et Biophysica Acta (BBA) - Bioenergetics 1364 (2): 271–86. May 1998. doi:10.1016/s0005-2728(98)00033-4. PMID 9593934. 
  15. ↑ "58 binary interactions found for search term NDUFS4". IntAct Molecular Interaction Database. EMBL-EBI. https://www.ebi.ac.uk/intact/interactions?conversationContext=3&query=NDUFS4. 

Further reading

  • "NDUFS4 mutations cause Leigh syndrome with predominant brainstem involvement". Molecular Genetics and Metabolism 97 (3): 185–9. July 2009. doi:10.1016/j.ymgme.2009.03.002. PMID 19364667. 
  • "The NADH: ubiquinone oxidoreductase (complex I) of the mammalian respiratory chain and the cAMP cascade". Journal of Bioenergetics and Biomembranes 34 (1): 1–10. February 2002. doi:10.1023/A:1013863018115. PMID 11860175. 
  • "Relationship between mitochondrial NADH-ubiquinone reductase and a bacterial NAD-reducing hydrogenase". Biochemistry 30 (8): 2166–75. February 1991. doi:10.1021/bi00222a021. PMID 1900194. 
  • "cDNA of eight nuclear encoded subunits of NADH:ubiquinone oxidoreductase: human complex I cDNA characterization completed". Biochemical and Biophysical Research Communications 253 (2): 415–22. December 1998. doi:10.1006/bbrc.1998.9786. PMID 9878551. 
  • "Human complex I defects can be resolved by monoclonal antibody analysis into distinct subunit assembly patterns". The Journal of Biological Chemistry 276 (12): 8892–7. March 2001. doi:10.1074/jbc.M009903200. PMID 11112787. 
  • "Mutation in the NDUFS4 gene of complex I abolishes cAMP-dependent activation of the complex in a child with fatal neurological syndrome". FEBS Letters 489 (2–3): 259–62. February 2001. doi:10.1016/S0014-5793(00)02334-6. PMID 11165261. 
  • "A nonsense mutation in the NDUFS4 gene encoding the 18 kDa (AQDQ) subunit of complex I abolishes assembly and activity of the complex in a patient with Leigh-like syndrome". Human Molecular Genetics 10 (5): 529–35. March 2001. doi:10.1093/hmg/10.5.529. PMID 11181577. 
  • "Resting oxygen consumption and in vivo ADP are increased in myopathy due to complex I deficiency". Neurology 58 (7): 1088–93. April 2002. doi:10.1212/wnl.58.7.1088. PMID 11940698. 
  • "A mitochondrial complex I defect impairs cold-regulated nuclear gene expression". The Plant Cell 14 (6): 1235–51. June 2002. doi:10.1105/tpc.010433. PMID 12084824. 
  • "The NDUFS4 nuclear gene of complex I of mitochondria and the cAMP cascade". Biochimica et Biophysica Acta (BBA) - Bioenergetics 1555 (1–3): 147–53. September 2002. doi:10.1016/S0005-2728(02)00270-0. PMID 12206907. 
  • "Genotyping microsatellite DNA markers at putative disease loci in inbred/multiplex families with respiratory chain complex I deficiency allows rapid identification of a novel nonsense mutation (IVS1nt -1) in the NDUFS4 gene in Leigh syndrome". Human Genetics 112 (5–6): 563–6. May 2003. doi:10.1007/s00439-002-0884-2. PMID 12616398. 
  • "Pathological mutations of the human NDUFS4 gene of the 18-kDa (AQDQ) subunit of complex I affect the expression of the protein and the assembly and function of the complex". The Journal of Biological Chemistry 278 (45): 44161–7. November 2003. doi:10.1074/jbc.M307615200. PMID 12944388. 
  • "Clinical heterogeneity in patients with mutations in the NDUFS4 gene of mitochondrial complex I". Journal of Inherited Metabolic Disease 26 (8): 813–5. 2004. doi:10.1023/B:BOLI.0000010003.14113.af. PMID 14765537. 
  • "Respiratory complex I in brain development and genetic disease". Neurochemical Research 29 (3): 547–60. March 2004. doi:10.1023/B:NERE.0000014825.42365.16. PMID 15038602. 
  • "Mutations in the NDUFS4 gene of mitochondrial complex I alter stability of the splice variants". FEBS Letters 579 (17): 3770–6. July 2005. doi:10.1016/j.febslet.2005.05.035. PMID 15975579. 
  • "Quantitative phosphoproteome analysis using a dendrimer conjugation chemistry and tandem mass spectrometry". Nature Methods 2 (8): 591–8. August 2005. doi:10.1038/nmeth776. PMID 16094384. 

This article incorporates text from the United States National Library of Medicine, which is in the public domain.



Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:NDUFS4&oldid=3500762"