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Structural determinants of protocadherin-15 elasticity and function in inner-ear mechanotransduction

Deepanshu Choudhary, Yoshie Narui, Brandon L. Neel, Lahiru N. Wimalasena, Carissa F. Klanseck, Pedro De-la-Torre, Conghui Chen, Raul Araya-Secchi, Elakkiya Tamilselvan, View ORCID ProfileMarcos Sotomayor
doi: https://doi.org/10.1101/695502
Deepanshu Choudhary
1Department of Chemistry and Biochemistry, The Ohio State University, 484 W 12th Avenue, Columbus, OH 43210
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Yoshie Narui
1Department of Chemistry and Biochemistry, The Ohio State University, 484 W 12th Avenue, Columbus, OH 43210
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Brandon L. Neel
1Department of Chemistry and Biochemistry, The Ohio State University, 484 W 12th Avenue, Columbus, OH 43210
2The Ohio State Biochemistry Program, The Ohio State University, 484 W 12th Avenue, Columbus, OH 43210
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Lahiru N. Wimalasena
1Department of Chemistry and Biochemistry, The Ohio State University, 484 W 12th Avenue, Columbus, OH 43210
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Carissa F. Klanseck
1Department of Chemistry and Biochemistry, The Ohio State University, 484 W 12th Avenue, Columbus, OH 43210
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Pedro De-la-Torre
1Department of Chemistry and Biochemistry, The Ohio State University, 484 W 12th Avenue, Columbus, OH 43210
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Conghui Chen
1Department of Chemistry and Biochemistry, The Ohio State University, 484 W 12th Avenue, Columbus, OH 43210
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Raul Araya-Secchi
1Department of Chemistry and Biochemistry, The Ohio State University, 484 W 12th Avenue, Columbus, OH 43210
3Structural Biophysics, Section for Neutron and X-ray Science, Niels Bohr Institute, University of Copenhagen, 2100 Copenhagen, Denmark
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Elakkiya Tamilselvan
1Department of Chemistry and Biochemistry, The Ohio State University, 484 W 12th Avenue, Columbus, OH 43210
4Biophysics Program, The Ohio State University, 484 W 12th Avenue, Columbus, OH 43210
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Marcos Sotomayor
1Department of Chemistry and Biochemistry, The Ohio State University, 484 W 12th Avenue, Columbus, OH 43210
2The Ohio State Biochemistry Program, The Ohio State University, 484 W 12th Avenue, Columbus, OH 43210
4Biophysics Program, The Ohio State University, 484 W 12th Avenue, Columbus, OH 43210
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  • ORCID record for Marcos Sotomayor
  • For correspondence: sotomayor.8@osu.edu
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Abstract

Protocadherin-15 (PCDH15), an atypical member of the cadherin superfamily, is essential for vertebrate hearing and its dysfunction has been associated with deafness and progressive blindness. The PCDH15 ectodomain, made of eleven extracellular cadherin (EC1-11) repeats and a membrane adjacent domain (MAD12), assembles as a parallel homodimer that interacts with cadherin-23 (CDH23) to form the tip link, a fine filament necessary for inner-ear mechanotransduction. Here we report X-ray crystal structures of a PCDH15 + CDH23 heterotetrameric complex and ten PCDH15 fragments that were used to build complete high-resolution models of the monomeric PCDH15 ectodomain. Using molecular dynamics (MD) simulations and validated crystal contacts we propose models for complete PCDH15 parallel homodimers and the tip-link bond. Steered MD simulations of these models predict their strength and suggest conditions in which a multimodal PCDH15 ectodomain can act as a stiff or soft gating spring. These results provide a detailed view of the first molecular steps in inner-ear sensory transduction.

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Posted July 08, 2019.
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Structural determinants of protocadherin-15 elasticity and function in inner-ear mechanotransduction
Deepanshu Choudhary, Yoshie Narui, Brandon L. Neel, Lahiru N. Wimalasena, Carissa F. Klanseck, Pedro De-la-Torre, Conghui Chen, Raul Araya-Secchi, Elakkiya Tamilselvan, Marcos Sotomayor
bioRxiv 695502; doi: https://doi.org/10.1101/695502
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Structural determinants of protocadherin-15 elasticity and function in inner-ear mechanotransduction
Deepanshu Choudhary, Yoshie Narui, Brandon L. Neel, Lahiru N. Wimalasena, Carissa F. Klanseck, Pedro De-la-Torre, Conghui Chen, Raul Araya-Secchi, Elakkiya Tamilselvan, Marcos Sotomayor
bioRxiv 695502; doi: https://doi.org/10.1101/695502

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