NDUFB6 explained

NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 6, also known as complex I-B17, is a protein that in humans is encoded by the NDUFB6 gene.^{[1] [2] [3]} NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 6, 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.^[4]

Gene

The NDUFB6 gene is located on the p arm of chromosome 9 in position 21.1 and is 19,659 base pairs long.^{[5] [6]}

Structure

The NDUFB6 protein weighs 15.5 kDa and is composed of 128 amino acids.^{[5] [6]} NDUFB6 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.^[4] 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.^[3] However, NDUFB6 is required for electron transfer activity.^[7] Mammalian complex I is composed of 44 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.^[3] 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

Decreased expression of genes involved in oxidative phosphorylation, including NDUFB6, is associated with insulin resistance and type 2 diabetes. A polymorphism in the promoter region of the NDFUB6 gene resulting in an adenine to guanine shift at rs629566 was shown to create a DNA methylation site that is associated with a decline in NDUFB6 expression in muscle of aging patients.^[8]

Further reading

• Smeitink J, van den Heuvel L . Human mitochondrial complex I in health and disease . American Journal of Human Genetics . 64 . 6 . 1505–10 . Jun 1999 . 10330338 . 1377894 . 10.1086/302432 .
• Earley FG, Ragan CI . Identification of the subunits of bovine heart mitochondrial NADH dehydrogenase that are exposed to the phospholipid bilayer by photo-labelling with 5-iodonaphth-1-yl azide . The Biochemical Journal . 191 . 2 . 429–36 . Nov 1980 . 7236204 . 1162233 . 10.1042/bj1910429.
• 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 . 415–22 . Dec 1998 . 9878551 . 10.1006/bbrc.1998.9786 .
• 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 . 1546–60 . Oct 2000 . 11042152 . 310934 . 10.1101/gr.140200 .
• Bénit P, Chretien D, Kadhom N, de Lonlay-Debeney P, Cormier-Daire V, Cabral A, Peudenier S, Rustin P, Munnich A, Rötig A . Large-scale deletion and point mutations of the nuclear NDUFV1 and NDUFS1 genes in mitochondrial complex I deficiency . American Journal of Human Genetics . 68 . 6 . 1344–52 . Jun 2001 . 11349233 . 1226121 . 10.1086/320603 .
• Vogel RO, Dieteren CE, van den Heuvel LP, Willems PH, Smeitink JA, Koopman WJ, Nijtmans LG . Identification of mitochondrial complex I assembly intermediates by tracing tagged NDUFS3 demonstrates the entry point of mitochondrial subunits . The Journal of Biological Chemistry . 282 . 10 . 7582–90 . Mar 2007 . 17209039 . 10.1074/jbc.M609410200 . free . 2066/52607 . free .

Notes and References

1. 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 . 115–9 . Nov 1998 . 9763677 . 10.1159/000015082 . 46818955 .
2. Smeitink J, Loeffen J, Smeets R, Triepels R, Ruitenbeek W, Trijbels F, van den Heuvel L . Molecular characterization and mutational analysis of the human B17 subunit of the mitochondrial respiratory chain complex I . Human Genetics . 103 . 2 . 245–50 . Aug 1998 . 9760212 . 10.1007/s004390050813 . 25046670 .
3. Web site: Entrez Gene: NDUFB6 NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 6, 17kDa.
4. Book: Donald . Voet . Judith G. . Voet . Charlotte W. . Pratt . vanc . 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 .
5. 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 .
6. Web site: NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 6 ]. Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) .
7. Loublier S, Bayot A, Rak M, El-Khoury R, Bénit P, Rustin P . The NDUFB6 subunit of the mitochondrial respiratory chain complex I is required for electron transfer activity: a proof of principle study on stable and controlled RNA interference in human cell lines . Biochemical and Biophysical Research Communications . 414 . 2 . 367–72 . Oct 2011 . 21964293 . 10.1016/j.bbrc.2011.09.078 .
8. Ling C, Poulsen P, Simonsson S, Rönn T, Holmkvist J, Almgren P, Hagert P, Nilsson E, Mabey AG, Nilsson P, Vaag A, Groop L . Genetic and epigenetic factors are associated with expression of respiratory chain component NDUFB6 in human skeletal muscle . The Journal of Clinical Investigation . 117 . 11 . 3427–35 . Nov 2007 . 17948130 . 10.1172/JCI30938 . 2030455.