Copper Chaperones

Starting from Ctr1

Let us continue the journey from Ctr1 to some intracellular copper chaperones.  The cyoplasmic loops might have their own gating functions, as suggested by Ren (2019), see Ctr1 post

Just looking at the sequences, there are a lot of arginines (R) and lysines (K) Fig 1C). Both of these are positively charged amino acids, just like Cu⁺.  Expasy has a tool for calculating the molecular weight and isoelectric point (pI) of sequences.   The isolelectric point is the pH at which the peptide has no net charge.  At the intracellular pH of 7.5,

• the first loop will have a net positive charge
• whereas the second loop will essentially be uncharged.

One may speculate that only when a chaperone neutralizes the positive charge on the first cyoplasmic loop will positively charged Cu⁺  be let out of the “gate.”

What is a chaperone?

A chaperone is a person who accompanies young people, on social occasions to prevent an illicit transfer of electrons. In some cases a protein chaperone refers to a protein that assists another protein in proper folding or unfolding. In the case of copper chaperones, both definitions are true. Copper chaperones prevent the illicit transfer of electrons from copper to molecular oxygen. They also assist in proper loading and folding of copper into proteins that use copper as a cofactor.

Reduced glutathione is included in this transport process (Hatori 2017).
Another twist to this story comes from the work of Maryon and coworkers. These authors demonstrated the need for a supply of reduced glutathione in order to facilitate loading of copper chaperones with copper. This suggests that only Cu+ can be loaded into the chaperones. It is curious that Ctr1 is usually depicted as wide at the intracellular lip. Is this so that copper chaperones can approach it to receive Cu⁺ or is this for glutathione access? HCH is another way of reiterating the histidine-cysteine-histidine motif.

Use of thiols to transfer Cu⁺

Our featured image shows two proteins engaged in a disulfide bond, just liked oxidized glutathione.  Copper chaperones do this in the process of transferring Cu⁺ .  We may get into the work of Banci and colleagues in a later post.

Cu⁺ transported down the affinity gradient.

Cu⁺  doesn’t stick around on the exit gate of Ctr1.  It travels from low affinity members of the “bucket  brigade” to high affinity enzymes. The Hatori publication has a clever way of visualizing this transfer.

• Abundance of  the Cu⁺ chaperone indicated by size of the elipse.
• Cu⁺  affinity indicated by the green color intensity.

Three main destinations of Cu⁺ 

1. Mitocondria: cytochrome C oxidase via Cox17
2. cytosol: Cu/Zn superoxide dismutase 1 via CCS
3. secreted proteins: lysyl oxidases (LOX),  ; DBH, dopamine-β-hydroxylase (DBH), Cu/Zn superoxide dismutase 3 (SOD3),  peptidylglycine-α-amidating monooxygenase (PAM) via Atox1 and ATP7A.

Metallothionein (MT) is a high affinity place to store excess copper.

Take home

From the entrance to Ctr1 to chaperones and insertion into enzymes, it is all about Cu⁺.  How enzymes use copper for functions necessary for health and life itself is another story for another post!  If you are interested in a copper supplement in the +1 oxidation state, visit the Mitosynergy store.

References

Banci L, Bertini I, Ciofi-Baffoni S, Janicka A, Martinelli M, Kozlowski H, Palumaa P.(2008)A structural-dynamical characterization of human Cox17. J Biol Chem. 283(12):7912-20.

Hatori Y, Inouye S, Akagi R.(2017) Thiol-based copper handling by the copper chaperone Atox1.IUBMB Life.69(4):246-254

Maryon EB, Molloy SA, Kaplan JH. (2013)Cellular glutathione plays a key role in copper uptake mediated by human copper transporter 1. Am J Physiol Cell Physiol. 304(8):C768-79.