Biology:NDUFA13

Short description: Protein-coding gene in the species Homo sapiens

Generic protein structure example

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 13 is an enzyme that in humans is encoded by the NDUFA13 gene. The NDUFA13 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.

Structure

The NDUFA13 gene is located on the p arm of chromosome 19 in position 13.2 and spans 11,995 base pairs. The gene produces a 17 kDa protein composed of 144 amino acids. NDUFA13 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. 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. 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.

Function

The human NDUFA13 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone. 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.

NDUFA13 has a homologous protein known as GRIM-19, a cell-death regulatory protein. It is involved in interferon/all-trans-retinoic acid (IFN/RA) induced cell death. This form of apoptotic activity is inhibited by interaction with viral IRF1. GRIM-19 prevents the transactivation of signal-transducer and activator of transcription 3 (STAT3) target genes but not other STAT family members.

Clinical significance

The homologous protein to NDUFA13, GRIM-19, may play a role in Crohn'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.

Interactions

NDUFA13 has been shown to interact with STAT3.

Further reading

• "Identification of novel human genes evolutionarily conserved in Caenorhabditis elegans by comparative proteomics.". Genome Res. 10 (5): 703–13. 2000. doi:10.1101/gr.10.5.703. PMID 10810093. 
• "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. 2000. doi:10.1089/107999000414844. PMID 10926209. 
• "Gene expression profiling in the human hypothalamus-pituitary-adrenal axis and full-length cDNA cloning.". Proc. Natl. Acad. Sci. U.S.A. 97 (17): 9543–8. 2000. doi:10.1073/pnas.160270997. PMID 10931946. Bibcode: 2000PNAS...97.9543H. 
• "GRIM-19, a cell death regulatory gene product, is a subunit of bovine mitochondrial NADH:ubiquinone oxidoreductase (complex I).". J. Biol. Chem. 276 (42): 38345–8. 2001. doi:10.1074/jbc.C100444200. PMID 11522775. 
• "Viral interferon regulatory factor 1 of Kaposi's sarcoma-associated herpesvirus interacts with a cell death regulator, GRIM19, and inhibits interferon/retinoic acid-induced cell death.". J. Virol. 76 (17): 8797–807. 2002. doi:10.1128/JVI.76.17.8797-8807.2002. PMID 12163600. 
• "The subunit composition of the human NADH dehydrogenase obtained by rapid one-step immunopurification.". J. Biol. Chem. 278 (16): 13619–22. 2003. doi:10.1074/jbc.C300064200. PMID 12611891. 
• "GRIM-19, a death-regulatory gene product, suppresses Stat3 activity via functional interaction.". EMBO J. 22 (6): 1325–35. 2003. doi:10.1093/emboj/cdg135. PMID 12628925. 
• "The cell death regulator GRIM-19 is an inhibitor of signal transducer and activator of transcription 3.". Proc. Natl. Acad. Sci. U.S.A. 100 (16): 9342–7. 2003. doi:10.1073/pnas.1633516100. PMID 12867595. Bibcode: 2003PNAS..100.9342Z. 
• "A protein interaction framework for human mRNA degradation.". Genome Res. 14 (7): 1315–23. 2004. doi:10.1101/gr.2122004. PMID 15231747. 
• "Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions.". Genome Res. 14 (9): 1711–8. 2004. doi:10.1101/gr.2435604. PMID 15342556. 
• "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. 2005. doi:10.1074/jbc.M413776200. PMID 15753091. 
• "Towards a proteome-scale map of the human protein-protein interaction network.". Nature 437 (7062): 1173–8. 2005. doi:10.1038/nature04209. PMID 16189514. Bibcode: 2005Natur.437.1173R. 
• "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. 2007. doi:10.1038/sj.cdd.4402004. PMID 16826196. 
• "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. 2007. doi:10.1074/jbc.M609410200. PMID 17209039. 

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