The NDUFA13 gene is located on the p arm of chromosome 19 in position 13.2 and spans 11,995 base pairs.[4] The gene produces a 17 kDa protein composed of 144 amino acids.[7] NDUFA13 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobictransmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site.[5] 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. NDUFA13 is one of about 31 hydrophobic subunits that form the transmembrane region of Complex I, but it is an accessory subunit that is believed not to be involved in catalysis.[8] The predicted secondary structure is primarily alpha helix, but the carboxy-terminal half of the protein has high potential to adopt a coiled-coil form. The amino-terminal part contains a putative beta sheet rich in hydrophobic amino acids that may serve as mitochondrial import signal.[4][6][9]
Function
The human NDUFA13 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone.[4]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.[5]
The homologous protein to NDUFA13, GRIM-19, may play a role in Chron's disease (CD), an inflammatory bowel disease (IBD) characterized by chronic inflammation of the intestinal epithelium. Its expression is decreased in the inflamed mucosa of patients with these diseases. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2), also known as caspase recruitment domain-containing protein 15 (CARD15) or inflammatory bowel disease protein 1 (IBD1), functions as a mammalian cytosolic pathogen recognition molecule and plays an anti-bacterial role by limiting survival of intracellular invasive bacteria. GRIM-19 acts as a downstream anti-bacterial effector in CARD15-mediated innate mucosal responses by regulating intestinal epithelial cell responses to microbes. Following NOD2-mediated recognition of bacterial muramyl dipeptide, GRIM-19 is required for NF-κB activation, a key component in regulating the immune response to infection.[8][10]
↑Hirst J, Carroll J, Fearnley IM, Shannon RJ, Walker JE (Jul 2003). "The nuclear encoded subunits of complex I from bovine heart mitochondria". Biochim Biophys Acta. 1604 (3): 135–50. doi:10.1016/S0005-2728(03)00059-8. PMID12837546.
↑Angell JE, Lindner DJ, Shapiro PS, Hofmann ER, Kalvakolanu DV (Nov 2000). "Identification of GRIM-19, a novel cell death-regulatory gene induced by the interferon-beta and retinoic acid combination, using a genetic approach". J Biol Chem. 275 (43): 33416–26. doi:10.1074/jbc.M003929200. PMID10924506.
↑ 5.05.15.2Pratt, Donald Voet, Judith G. Voet, Charlotte W. (2013). "18". Fundamentals of biochemistry : life at the molecular level (4th ed.). Hoboken, NJ: Wiley. pp. 581–620. ISBN9780470547847.
↑ 6.06.1Emahazion T, Beskow A, Gyllensten U, Brookes AJ (Nov 1998). "Intron based radiation hybrid mapping of 15 complex I genes of the human electron transport chain". Cytogenet Cell Genet. 82 (1–2): 115–9. doi:10.1159/000015082. PMID9763677.
↑Ton C, Hwang DM, Dempsey AA, Liew CC (Jan 1998). "Identification and primary structure of five human NADH-ubiquinone oxidoreductase subunits". Biochem Biophys Res Commun. 241 (2): 589–94. doi:10.1006/bbrc.1997.7707. PMID9425316.
↑Barnich, N; Hisamatsu, T; Aguirre, JE; Xavier, R; Reinecker, HC; Podolsky, DK (13 May 2005). "GRIM-19 interacts with nucleotide oligomerization domain 2 and serves as downstream effector of anti-bacterial function in intestinal epithelial cells". The Journal of Biological Chemistry. 280 (19): 19021–6. doi:10.1074/jbc.m413776200. PMID15753091.
Chidambaram NV, Angell JE, Ling W, Hofmann ER, Kalvakolanu DV (2000). "Chromosomal localization of human GRIM-19, a novel IFN-beta and retinoic acid-activated regulator of cell death". J. Interferon Cytokine Res. 20 (7): 661–5. doi:10.1089/107999000414844. PMID10926209.
Murray J, Zhang B, Taylor SW, Oglesbee D, Fahy E, Marusich MF, Ghosh SS, Capaldi RA (2003). "The subunit composition of the human NADH dehydrogenase obtained by rapid one-step immunopurification". J. Biol. Chem. 278 (16): 13619–22. doi:10.1074/jbc.C300064200. PMID12611891.
Barnich N, Hisamatsu T, Aguirre JE, Xavier R, Reinecker HC, Podolsky DK (2005). "GRIM-19 interacts with nucleotide oligomerization domain 2 and serves as downstream effector of anti-bacterial function in intestinal epithelial cells". J. Biol. Chem. 280 (19): 19021–6. doi:10.1074/jbc.M413776200. PMID15753091.
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 (2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. doi:10.1038/nature04209. PMID16189514.
Huang G, Chen Y, Lu H, Cao X (2007). "Coupling mitochondrial respiratory chain to cell death: an essential role of mitochondrial complex I in the interferon-beta and retinoic acid-induced cancer cell death". Cell Death Differ. 14 (2): 327–37. doi:10.1038/sj.cdd.4402004. PMID16826196.
Vogel RO, Dieteren CE, van den Heuvel LP, Willems PH, Smeitink JA, Koopman WJ, Nijtmans LG (2007). "Identification of mitochondrial complex I assembly intermediates by tracing tagged NDUFS3 demonstrates the entry point of mitochondrial subunits". J. Biol. Chem. 282 (10): 7582–90. doi:10.1074/jbc.M609410200. PMID17209039.