Proteins and Copper Ions: Unraveling Their Intimate Relationship

Yoshiaki Furukawa (Associate Professor, Department of Chemistry)

What comes to mind when you hear the word “copper”? Many of you probably think of the 10-yen coins in your hand or perhaps Olympic medals. However, the students in my Laboratory of Mechanistic Biochemistry are a little different from you; they would likely answer “proteins” (I hope!). Proteins are organic macromolecules composed of 20 types of amino acids and may seem to have no connection with metals, a prime example of inorganic substances. In reality, however, many proteins exhibit biological activity only after binding to metal ions. Copper ions are especially important; the very reason you are breathing and alive at this moment is thanks to a certain protein that binds to and functions with copper ions. Furthermore, a protein called SOD1, which we study in our lab, plays a crucial role in protecting the body from oxidative damage by binding to copper ions (Figure 1). In other words, understanding the mechanism of how proteins find and bind to their small partners, copper ions, within the cell leads to understanding the essence of many life phenomena.

Copper is a rare metal, making up only 0.00007% of the Earth's crust, which might explain to some extent why it is so frequently stolen. However, it is not well understood why living organisms have chosen such a rare metal ion as a factor so crucial that it is a matter of life and death. Interestingly, archaea, which do not require oxygen for growth, seem to lack copper-binding proteins. This suggests that organisms may have been forced to utilize copper ions due to the dramatic environmental change about 3 billion years ago when oxygen levels on Earth rapidly increased. However, in the current oxygen-rich environment, copper ions can become a source of reactive oxygen species that damage DNA and cell membranes. Therefore, a situation where copper ions exist freely within the cell must be avoided at all costs. To achieve this, copper ions are transported within the cell from one specific protein to another, much like a bucket brigade. Using the SOD1 protein as an example, I have been working to elucidate the mechanisms that control the operation of this “copper ion transport network” (Figure 2).

Furthermore, we have proposed that if a part of this network malfunctions, proteins may form abnormally associated aggregates, potentially leading to the onset of a neurodegenerative disease called amyotrophic lateral sclerosis (ALS) (Figure 3). In fact, it has been reported that fibrous aggregates composed of SOD1, as shown in the figure, accumulate in the motor neurons of some ALS patients. When I think about the relationship between proteins and copper ions, my days are filled with endless intellectual curiosity, from pondering ancient times to hoping that our findings could be applied to treatments for neurodegenerative diseases.

I am a big fan of Sherlock Holmes. His words and actions, which show his insistence on logical thinking, as exemplified by his famous line, “I am a brain, Watson. The rest of me is a mere appendix,” teach us many things necessary for understanding proteins, the subject of our research. For example, there is a scene where Holmes brilliantly deduces where a client who has come to his room has traveled from. This is not an elaborate trick, but simply a matter of Holmes instantly comparing the nature of the mud on the client's shoes with his memorized knowledge of the soil characteristics throughout London to deduce the client's movements. In other words, against a backdrop of vast knowledge, and with sharp powers of observation and imagination, he logically derives a grand truth from tiny fragments of fact. I would love to hear Holmes's reasoning just once on where and how our “clients,” the proteins, picked up the “mud” of copper ions.