Summary: For the first time, researchers have captured in near-atomic detail the structure of a key part of the inner ear responsible for hearing. The results could pave the way for developing new treatments for those with hearing impairments.
Source: Oregon Health and Science University
Scientists at Oregon Health & Science University have revealed, for the first time and in near-atomic detail, the structure of the key part of the inner ear responsible for hearing.
“This is the last sensory system in which that fundamental molecular machinery has remained unknown,” said senior author Eric Gouaux, Ph.D., senior scientist with the OHSU Vollum Institute and a Howard Hughes Medical Institute investigator. “The molecular machinery that carries out this absolutely amazing process has been unresolved for decades.”
The researchers made the discovery by teasing out the structure through years of painstaking research to isolate the process that enables the inner ear to convert vibrations into sound, known as the mechanosensory transduction complex.
The study, which revealed the structure through cryo-electron microscopy, published today in the journal Nature. The findings could point the way toward developing new treatments for hearing impairments, which affect more than 460 million people worldwide.
The discovery reveals the architecture of the inner ear complex that converts vibrations into electrical impulses that the brain translates as sound. Known as mechanosensory transduction, the process is responsible for the sensations of balance and sound.
Scientists exploited the fact that the roundworm Caenorhabditis elegans harbors a mechanosensory complex very similar to that of humans.
Resolving the basic structure is the first step, according to Gouaux.
“It immediately suggests mechanisms by which one might be able to compensate for those deficits,” Gouaux said. “If a mutation gives rise to a defect in the transduction channel that causes hearing loss, it’s possible to design a molecule that fits into that space and rescues the defect. Or it may mean we can strengthen interactions that have been weakened.”
The findings could point the way toward developing new treatments for hearing impairments, which affect more than 460 million people worldwide. Image is in the public domain
Hearing loss can be inherited through gene mutations that alter the proteins comprising the mechanosensory transduction complex. Or it can occur from damage, including sustained exposure to loud noise. In either case, OHSU researchers’ discovery allows scientists to visualize the complex for the first time.
The finding is an extraordinary achievement, said one leading neuroscience researcher at OHSU who was not directly involved in the research.
“The auditory neuroscience field has been waiting for these results for decades, and now that they are right here—we are ecstatic,” said Peter Barr-Gillespie, Ph.D., an OHSU research scientist and national leader in hearing research. “The results from this paper immediately suggest new avenues of research, and so will invigorate the field for years to come.”
Barr-Gillespie also serves as chief research officer and executive vice president at OHSU.
Researchers resolved the puzzle through careful cultivation and isolation techniques involving 60 million worms over almost five years.
“We spent several years optimizing worm-growth and protein-isolation methods, and had many ‘rock-bottom’ moments when we considered giving up,” co-first author Sarah Clark, Ph.D., a postdoctoral fellow in the Gouaux lab, wrote in a research brief published by Nature.
Hanbin Jeong, Ph.D., a postdoc fellow in the Gouaux lab, is co-first author with Clark. Co-authors included April Goehring, senior research associate in the Gouaux lab; and, Sepehr Dehghani-Ghahnaviyeh, Ali Rasouli, and Emad Tajkhorshid of the University of Illinois at Urbana-Champaign.
Structure of C. elegans TMC-1 complex illuminates auditory mechanosensory transduction
The initial step in the sensory transduction pathway underpinning hearing and balance in mammals involves the conversion of force into the gating of a mechanosensory transduction channel.
Despite the profound socioeconomic impacts of hearing disorders and the fundamental biological significance of understanding mechanosensory transduction, the composition, structure and mechanism of the mechanosensory transduction complex have remained poorly characterized.
Here we report the single-particle cryo-electron microscopy structure of the native transmembrane channel-like protein 1 (TMC-1) mechanosensory transduction complex isolated from Caenorhabditis elegant.
The two-fold symmetric complex is composed of two copies each of the pore-forming TMC-1 subunit, the calcium-binding protein CALM-1 and the transmembrane inner ear protein TMIE.
CALM-1 makes extensive contacts with the cytoplasmic face of the TMC-1 subunits, whereas the single-pass TMIE subunits reside on the periphery of the complex, poised like the handles of an accordion. A subset of complexes additionally includes a single arrestin-like protein, arrestin domain protein (ARRD-6), bound to a CALM-1 subunit.
Single-particle reconstructions and molecular dynamics simulations show how the mechanosensory transduction complex deforms the membrane bilayer and suggest crucial roles for lipid–protein interactions in the mechanism by which mechanical force is transduced to ion channel gating.