COX6A1

Structure

The COX6A1 gene, located on the q arm of chromosome 12 in position 24.2, contains 3 exons and is 2,653 base pairs in length. The COX6A1 protein weighs 12 kDa and is composed of 109 amino acids. The protein is a subunit of Complex IV, a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. This nuclear gene encodes polypeptide 1 (liver isoform) of subunit VIa, and polypeptide 1 is found in all non-muscle tissues. Polypeptide 2 (heart/muscle isoform) of subunit VIa is encoded by a different gene, COX6A2, and is present only in striated muscles. These two polypeptides share 66% amino acid sequence identity.

Function

Cytochrome c oxidase (COX) is the terminal enzyme of the mitochondrial respiratory chain. It is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome c to molecular oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane to drive ATP synthesis via protonmotive force. The mitochondrially-encoded subunits perform the electron transfer of proton pumping activities. The functions of the nuclear-encoded subunits are unknown but they may play a role in the regulation and assembly of the complex.

Summary reaction: : 4 Fe2+-cytochrome c + 8 H+in + O2 → 4 Fe3+-cytochrome c + 2 H2O + 4 H+out

Clinical significance

A mutation leading to a 5 base pair deletion in the COX6A1 gene is associated with Charcot-Marie-Tooth disease (CMT). CMT is the most common inherited neuropathy and can result from mutations in over 30 different loci. Expression of COX6A1 is significantly reduced in affected individuals.

The Trans-activator of transcription protein (Tat) of human immunodeficiency virus (HIV) inhibits cytochrome c oxidase (COX) activity in permeabilized mitochondria isolated from both mouse and human liver, heart, and brain samples. Rapid loss of membrane potential (ΔΨm) occurs with submicromolar doses of Tat, and cytochrome c is released from the mitochondria.

References

References

1. "Entrez Gene: COX6A1 cytochrome c oxidase subunit VIa polypeptide 1".
2. (Sep 1997). "Assignment of COX6A1 to 6p21 and a pseudogene (COX6A1P) to 1p31.1 by in situ hybridization and somatic cell hybrids". Cytogenetics and Cell Genetics.
3. (Oct 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research.
4. "Cytochrome c oxidase subunit 6A1, mitochondrial". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
5. (2013). "Fundamentals of biochemistry: life at the molecular level". Wiley.
6. (Sep 2014). "A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease". American Journal of Human Genetics.
7. (2012). "HIV-1 Tat protein directly induces mitochondrial membrane permeabilization and inactivates cytochrome c oxidase". Cell Death & Disease.