Sounding out the protein that enables us to hear

The proposed structure of the TMC1 protein (not to scale), superimposed over rows of hair cells in the mouse inner ear. The yellow portions indicate the amino acid substitutions used to identify the location of the pore that admits ions into the cell. (CREDIT: Bifeng Pan et al., Neuron 2018, https://doi.org/10.1016/j.neuron.2018.07.033)

In 2011, a team led by Jeffrey Holt, PhD, demonstrated that a protein called TMC1 is required for hearing and balance, following the 2002 discovery that mutations in the TMC1 gene cause deafness. Holt’s team proposed that TMC1 proteins form channels that enable electrically charged ions such as calcium and potassium to enter the delicate hair cells of the inner ear. This, in turn, enables the cells to convert sound waves and head movement into electrical signals that talk to the brain.

In a new study published today in Neuron, Holt and colleagues teamed with the lab of David Corey, PhD, at Harvard Medical School. Together, they confirmed TMC1’s essential role in hearing, ending a 40-year quest, and mapped out its working parts.

Working with living hair cells in mice, they made substitutions in 17 amino acids within the TMC1 protein, one at a time, to see which substitutions altered hair cells’ ability to respond to stimuli and allow the flow of ions. Eleven amino acid substitutions altered the influx of ions, and five did so dramatically, reducing ion flow by up to 80 percent. One substitution blocked calcium flow completely, thereby revealing the location of the pore within TMC1 that enables ion influx.

Down the road, the study could have implications for reversing hearing loss, which affects more than 460 million people worldwide.

“To design optimal treatments for hearing loss, we need to know the molecules and their structures where disease-causing malfunctions arise, and our findings are an important step in that direction,” Holt said in this press release from Harvard Medical School.

Read more about Holt’s work.