Characterizing the Evolution of a Cadherin Bond Involved in Sensory Perception

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The Ohio State University

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Vertebrate hair cells have evolved over 500 million years to function as the exquisitely precise and robust mechanosensors that we see in humans today. These hair cells transform mechanical stimuli into electrochemical signals for brain processing, ultimately allowing hearing to occur. Facilitating this process are bundles of small hair-like structures referred to as stereocilia that are present at the apical surface of hair cells in the inner ear. Connecting each stereocilium to its neighbor on this bundle is the tip link, a protein filament which gates ion channels. When sound vibrations stimulate the inner ear, these bundles are deflected, and tip links are stretched. This stretching triggers the flow of potassium ions through ion channels, which ultimately allows for sound waves to be converted into electrical impulses for the brain to interpret. In vertebrates, two proteins, cadherin-23 (CDH23) and protocadherin-15 (PCDH15) interact with one another to form tip links. Each of these proteins has numerous extracellular cadherin (EC) repeats crucial for adhesion. X-ray crystal structures of mouse protein fragments have demonstrated that this interaction is mediated by the protein tips (EC1-2), which engage in an antiparallel "handshake complex". Additional in vivo and in vitro experiments along with genetic analyses illustrate that this handshake complex is essential for hearing to occur for both mice and humans. However, our understanding of this vital filament in non-mammalian species remains limited. Here, a range of biochemical techniques were utilized to begin to characterize the evolutionary path of this protein complex. Our results suggest a fundamental binding mechanism between CDH23 and PCDH15 throughout all vertebrates and paralogs, despite evolutionary sequence variations. Our work asserts that while the CDH23 and PCDH15 interaction seems to be universally conserved, distinct biophysical properties, such as complex strength and rate of binding, may vary among different vertebrate lineages. Furthermore, high-speed atomic force microscopy imaging was utilized to characterize full-length PCDH15 ectodomain paralogs in fish, revealing intriguing structural attributes.


My work on this project was catalyzed by a previous graduate student, Dr. Collin Nisler, who selected the non-mammalian species I worked with and ordered the template DNA of my construct. The protein structure that I determined was published in a paper with Dr. Nisler, where he is first author, and I am co-second author.


Cadherins, Evolution, Hearing, Tip link, Usher syndrome, Vision loss