Biology:NDUFA2

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

Generic protein structure example

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 2 is a protein that in humans is encoded by the NDUFA2 gene. The NDUFA2 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. Mutations in the NDUFA2 gene are associated with Leigh's syndrome.

Structure

The NDUFA2 gene is located on the long (q) arm of chromosome 5 at position 31.2 and it spans 2,422 base pairs. The NDUFA2 gene produces an 11 kDa protein composed of 99 amino acids. NDUFA2 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. NDUFA2 is one of about 31 hydrophobic subunits that form the transmembrane region of Complex I. 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:ubiquinone oxidoreductase complex at the inner mitochondrial membrane.

Function

The human NDUFA2 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone. NDUFA2 is an accessory subunit of Complex I that is believed not to be involved in catalysis but may be involved in regulating Complex I activity or its assembly via assistance in redox processes. 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

Mutations in the NDUFA2 gene can result in Leigh's syndrome, a severe neurological disorder that typically arises in the first year of life. One such mutation interferes with normal splicing patterns and results in exon 2 being skipped. This causes a reduction in Complex I activity and disturbs its assembly. The NDUFA2 mutation is also associated with the depolarization of the mitochondria.

Interactions

NDUFA2 has many protein interactions, including interactions with other members of the NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, other subunits of Complex I as well as with redox proteins. This may be due to its potential role in Complex I assembly and assistance in redox processes.

Further reading

• "Sequences of 20 subunits of NADH:ubiquinone oxidoreductase from bovine heart mitochondria. Application of a novel strategy for sequencing proteins using the polymerase chain reaction". Journal of Molecular Biology 226 (4): 1051–72. Aug 1992. doi:10.1016/0022-2836(92)91052-Q. PMID 1518044. 
• "In situ hybridisation mapping of genomic clones for five human respiratory chain complex I genes". Cytogenetics and Cell Genetics 78 (1): 21–4. 1997. doi:10.1159/000134618. PMID 9345899. 
• "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. doi:10.1006/bbrc.1998.9786. PMID 9878551. 
• "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. doi:10.1101/gr.140200. PMID 11042152. 
• "The oxidized subunit B8 from human complex I adopts a thioredoxin fold". Structure 12 (9): 1645–54. Sep 2004. doi:10.1016/j.str.2004.06.021. PMID 15341729. 
• "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. doi:10.1074/jbc.M609410200. PMID 17209039.