NDUFB9 explained

NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 9 is an enzyme that in humans is encoded by the NDUFB9 gene.^{[1] [2]} NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 9 is an accessory subunit of the NADH dehydrogenase (ubiquinone) complex, located in the mitochondrial inner membrane. It is also known as Complex I and is the largest of the five complexes of the electron transport chain.^[3]

Structure

The NDUFB9 gene is located on the q arm of chromosome 8 in position 13.3 and is 10,884 base pairs long. The NDUFB9 protein weighs 22 kDa and is composed of 179 amino acids.^{[4] [5]} NDUFB9 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site.^[3] It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane.

Function

The protein encoded by this gene is an accessory subunit of the multisubunit NADH:ubiquinone oxidoreductase (complex I) that is not directly involved in catalysis. Mammalian complex I is composed of 45 different subunits. It locates at the mitochondrial inner membrane. This protein complex has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. Alternative splicing occurs at this locus and two transcript variants encoding distinct isoforms have been identified.^[2] Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH₂. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH₂). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.

Clinical significance

A mutation in NDUFB9 resulting in reduction in NDUFB9 protein and both amount and activity of complex I has been shown to be a causal mutation leading to Complex I deficiency.^[6]

Further reading

• Emahazion T, Beskow A, Gyllensten U, Brookes AJ . Intron based radiation hybrid mapping of 15 complex I genes of the human electron transport chain . Cytogenetics and Cell Genetics . 82 . 1-2 . 115–119 . 1998 . 9763677 . 10.1159/000015082 . 46818955 .
• Loeffen JL, Triepels RH, van den Heuvel LP, Schuelke M, Buskens CA, Smeets RJ, Trijbels JM, Smeitink JA . cDNA of eight nuclear encoded subunits of NADH:ubiquinone oxidoreductase: human complex I cDNA characterization completed . Biochemical and Biophysical Research Communications . 253 . 2 . 415–422 . December 1998 . 9878551 . 10.1006/bbrc.1998.9786 .
• Lin X, Wells DE, Kimberling WJ, Kumar S . Human NDUFB9 gene: genomic organization and a possible candidate gene associated with deafness disorder mapped to chromosome 8q13 . Human Heredity . 49 . 2 . 75–80 . March 1999 . 10077726 . 10.1159/000022848 . 25197216 .
• Dias Neto E, Correa RG, Verjovski-Almeida S, Briones MR, Nagai MA, da Silva W, Zago MA, Bordin S, Costa FF, Goldman GH, Carvalho AF, Matsukuma A, Baia GS, Simpson DH, Brunstein A, de Oliveira PS, Bucher P, Jongeneel CV, O'Hare MJ, Soares F, Brentani RR, Reis LF, de Souza SJ, Simpson AJ . Shotgun sequencing of the human transcriptome with ORF expressed sequence tags . Proceedings of the National Academy of Sciences of the United States of America . 97 . 7 . 3491–3496 . March 2000 . 10737800 . 16267 . 10.1073/pnas.97.7.3491 . free . 2000PNAS...97.3491D .
• Ye Z, Connor JR . cDNA cloning by amplification of circularized first strand cDNAs reveals non-IRE-regulated iron-responsive mRNAs . Biochemical and Biophysical Research Communications . 275 . 1 . 223–227 . August 2000 . 10944468 . 10.1006/bbrc.2000.3282 .
• Zhang QH, Ye M, Wu XY, Ren SX, Zhao M, Zhao CJ, Fu G, Shen Y, Fan HY, Lu G, Zhong M, Xu XR, Han ZG, Zhang JW, Tao J, Huang QH, Zhou J, Hu GX, Gu J, Chen SJ, Chen Z . Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells . Genome Research . 10 . 10 . 1546–1560 . October 2000 . 11042152 . 310934 . 10.1101/gr.140200 .
• Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S, Timm J, Mintzlaff S, Abraham C, Bock N, Kietzmann S, Goedde A, Toksöz E, Droege A, Krobitsch S, Korn B, Birchmeier W, Lehrach H, Wanker EE . A human protein-protein interaction network: a resource for annotating the proteome . Cell . 122 . 6 . 957–968 . September 2005 . 16169070 . 10.1016/j.cell.2005.08.029 . free . 8235923 . 11858/00-001M-0000-0010-8592-0 .
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–1178 . October 2005 . 16189514 . 10.1038/nature04209 . 4427026 . 2005Natur.437.1173R .

Notes and References

1. Gu JZ, Lin X, Wells DE . The human B22 subunit of the NADH-ubiquinone oxidoreductase maps to the region of chromosome 8 involved in branchio-oto-renal syndrome . Genomics . 35 . 1 . 6–10 . Sep 1996 . 8661098 . 10.1006/geno.1996.0316 .
2. Web site: Entrez Gene: NDUFB9 NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 9, 22kDa.
3. Book: Voet DM, Voet JG, Pratt CW . Donald Voet . Judith G. Voet . Fundamentals of biochemistry: life at the molecular level . 2013 . Wiley . Hoboken, NJ . 978-0-470-54784-7 . Chapter 18 . 581–620 . 4th .
4. Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P . Integration of cardiac proteome biology and medicine by a specialized knowledgebase . Circulation Research . 113 . 9 . 1043–53 . Oct 2013 . 23965338 . 4076475 . 10.1161/CIRCRESAHA.113.301151 .
5. Web site: NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 9 ]. Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) .
6. Haack TB, Madignier F, Herzer M, Lamantea E, Danhauser K, Invernizzi F, Koch J, Freitag M, Drost R, Hillier I, Haberberger B, Mayr JA, Ahting U, Tiranti V, Rötig A, Iuso A, Horvath R, Tesarova M, Baric I, Uziel G, Rolinski B, Sperl W, Meitinger T, Zeviani M, Freisinger P, Prokisch H . Mutation screening of 75 candidate genes in 152 complex I deficiency cases identifies pathogenic variants in 16 genes including NDUFB9 . Journal of Medical Genetics . 49 . 2 . 83–89 . February 2012 . 22200994 . 10.1136/jmedgenet-2011-100577 . 13907809 .