Molecular Mechanics of Hearing
| Date/Time: | Monday, 04 Dec 2017 from 4:10 pm to 5:00 pm |
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| Location: | Phys 0003 |
| Phone: | 515-294-5441 |
| Channel: | College of Liberal Arts and Sciences |
| Actions: | Download iCal/vCal | Email Reminder |
Abstract: Cadherins form a large superfamily of proteins essential for morphogenesis, neuronal connectivity, and tissue integrity. Two atypical members of this superfamily, cadherin-23 (cdh23) and protocadherin-15 (pcdh15) are also involved in hereditary deafness and blindness. In the inner ear, these two proteins interact to form the tip link, a fine filament that pulls open transduction channels to initiate a cascade of events leading to sensory perception. Here we present structural, computational, and biophysical experiments that reveal unique properties of the tip-link's extracellular cadherin (EC) repeats. Our crystal structures, simulations, and binding assays show how the N-terminus of pcdh15 and several of its variants form a calcium-dependent heterophilic complex with the N-terminus of cdh23. In addition, structures and simulations of other domains of cdh23 and pcdh15 reveal unusual inter-repeat linker regions that may alter the tertiary structure elasticity of these proteins. Overall, our results provide a molecular view of tip-link mechanics and identify the structural determinants of cdh23 and pcdh15 function in vertebrate mechanosensation.
Bio: Marcos Sotomayor received his B.Sc. in Physics from Universidad de Chile in 2001 and his Ph.D. in Physics from the University of Illinois at Urbana-Champaign in 2007. As a graduate student with Dr. Klaus Schulten in the theoretical and computational biophysics group, he did molecular dynamics simulations of proteins involved in mechanotransduction. His computational studies predicted the conductance of the ion channel MscS structure, as well as the elasticity of ankyrin and cadherin repeats. After finishing his Ph.D., he joined the laboratories of David P. Corey and Rachelle Gaudet to do experimental work as a postdoctoral researcher at Harvard University. There he solved the first X-ray crystal structure of a heterophilic cadherin complex essential for hearing and balance. During his postdoctoral tenure, he was a Howard Hughes Medical Institute fellow of the Helen Hay Whitney foundation. Marcos received a prestigious NIH K99/R00 award and started at OSU in July of 2013. In 2015, he received a Distinguished Undergraduate Research Mentor award from the undergraduate research office at OSU and was selected as an Alfred P. Sloan Research Fellow in Neuroscience.