Structural Biochemistry/Copper Metallochaperones

A "free" copper is a thermodynamic term that corresponds to aquo Cu(I) or Cu(II) complexes without binding to ligands such as amino acids or biopolymers. Free intracellular copper ions can also be defined in kinetic terms: less than 0.01 percent of total cellular copper can become free in the cytoplasm during the cell's lifetime. Copper chelation capacity becomes potent when copper detoxification systems such as metallothioneins are induced. Metallochaperones succeed in acquiring the metal and donating it to enzymes that need it. There are three different copper trafficking pathways discovered for copper.

Three Pathways

Pathway 1: Copper to Mitochondria A mitochondrial enzyme named Cytochrome oxidase requires three copper ions to be inserted into two subunits: a binuclear copper site protruding into the inner membrane space of the mitochondria and a mononuclear site buried within the inner membrane. Among the host of assembly factors required for cytochrome oxidase activity, two proteins have an effect on copper utilization.

Pathway 2: ATX1 Pathway of Copper to Golgi

Proposed pathway for copper transfer from ATX1 to CCC2

ATX1 was found to deliver copper to an intracellular copper transporter located in the Golgi compartment. Then the copper transporter can pump the metal into the lumen of the Golgi for insertion into copper enzymes destined on cell surface. Specially, copper delivered by ATX1 are targeted by P-type copper transporters which conserved in eukaryotes. P-type copper transporters can transport ATPase. Human beings specially have two types of transporters which are ATP7A and ATP7B.

Pathway 3: Copper to Cytosolic Superoxide Dismutase

Cytosolic Superoxide Dismutase specially targer copper with enzyme SOD1. The enzyme SOD1 protects cells from oxidative damage under toxic superoxide anion radicals in redox reactions of copper ions. The insertion of copper into SOD1 requires a copper metallochaperone involved in the lysine biosynthetic pathway, known as LYS7. CCS is the largest of copper metallochaperones discovered so far. Whereas ATX1 and COX17 are defined in domain with single protein, CCS can be defined in three different domains.

Metallochaperones in Prokaryotes

Prokaryotes do not have intracellular compartmentalization usually presents in eukaryotes; therefore metal carriers such as COX17 may not be useful. A homologue to ATX1 was discovered against enteric bacteria. CopZ was originally proposed to function as a copper transcription factor, it is also a copper metallochaperone. Purified CopZ can transfer copper displaces the zinc ion needed for CopY binding to DNA.

The analogous trafficking pathways also exist for other metals. Other than copper for the delivery of iron to the sites of iron-sulfur cluster assembly, other groups such as the IscA family of proteins also perform the similar functions. Other than that, prokaryotic nickel-binding proteins may also facilitate the insertion of the metal into nickel-requiring enzymes, such as urease and cobalt dehydrogenase.

Conclusion

Metallochaperones are critical for determing cell function under copper conditions. Metallochaperones ensure the safe delivery of the metal ion to proper intracellular destination and also protect the cargo from adventitious reactions.

References

Thomas V. O'Halloran and Valeria Cizewski Culotta "Metallochaperones, an Intracellular Shuttle Service for Metal Ions"