Structural determinants of protocadherin-15 mechanics and function in hearing and balance perception
Abstract
The vertebrate inner ear, responsible for hearing and balance, is able to sense minute mechanical stimuli originating from an extraordinarily broad range of sound frequencies and intensities or from head movements. Integral to these processes is the tip-link protein complex, which conveys force to open the inner-ear transduction channels that mediate sensory perception. Protocadherin-15 and cadherin-23, two atypically large cadherins with 11 and 27 extracellular cadherin (EC) repeats, are involved in deafness and balance disorders and assemble as parallel homodimers that interact to form the tip link. Here we report the X-ray crystal structure of a protocadherin-15 + cadherin-23 heterotetrameric complex at 2.9-Å resolution, depicting a parallel homodimer of protocadherin-15 EC1-3 molecules forming an antiparallel complex with two cadherin-23 EC1-2 molecules. In addition, we report structures for 10 protocadherin-15 fragments used to build complete high-resolution models of the monomeric protocadherin-15 ectodomain. Molecular dynamics simulations and validated crystal contacts are used to propose models for the complete extracellular protocadherin-15 parallel homodimer and the tip-link bond. Steered molecular dynamics simulations of these models suggest conditions in which a structurally diverse and multimodal protocadherin-15 ectodomain can act as a stiff or soft gating spring. These results reveal the structural determinants of tip-link–mediated inner-earmore »
- Authors:
-
[1];
[1];
[1];
[1];
[1];
[1];
[1];
[2];
[1];
[1]
- The Ohio State Univ., Columbus, OH (United States)
- The Ohio State Univ., Columbus, OH (United States); Univ. of Copenhagen (Denmark)
- Publication Date:
- Research Org.:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- National Institutes of Health (NIH); National Institute on Deafness and Other Communication Disorders (NIDCD); National Science Foundation (NSF); USDOE Office of Science (SC), Biological and Environmental Research (BER)
- OSTI Identifier:
- 1691539
- Grant/Contract Number:
- AC02-06CH11357; GUP 40277; 49774; 59251; NIGMS P30 GM124169 ALS-ENABLE; S10OD018483
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Proceedings of the National Academy of Sciences of the United States of America
- Additional Journal Information:
- Journal Volume: 117; Journal Issue: 40; Journal ID: ISSN 0027-8424
- Publisher:
- National Academy of Sciences
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; auditory system; hair cell; tip link; mechanotransduction; PCDH15
Citation Formats
Choudhary, Deepanshu, Narui, Yoshie, Neel, Brandon L., Wimalasena, Lahiru N., Klanseck, Carissa F., De-la-Torre, Pedro, Chen, Conghui, Araya-Secchi, Raul, Tamilselvan, Elakkiya, and Sotomayor, Marcos. Structural determinants of protocadherin-15 mechanics and function in hearing and balance perception. United States: N. p., 2020.
Web. doi:10.1073/pnas.1920444117.
Choudhary, Deepanshu, Narui, Yoshie, Neel, Brandon L., Wimalasena, Lahiru N., Klanseck, Carissa F., De-la-Torre, Pedro, Chen, Conghui, Araya-Secchi, Raul, Tamilselvan, Elakkiya, & Sotomayor, Marcos. Structural determinants of protocadherin-15 mechanics and function in hearing and balance perception. United States. https://doi.org/10.1073/pnas.1920444117
Choudhary, Deepanshu, Narui, Yoshie, Neel, Brandon L., Wimalasena, Lahiru N., Klanseck, Carissa F., De-la-Torre, Pedro, Chen, Conghui, Araya-Secchi, Raul, Tamilselvan, Elakkiya, and Sotomayor, Marcos. Tue .
"Structural determinants of protocadherin-15 mechanics and function in hearing and balance perception". United States. https://doi.org/10.1073/pnas.1920444117. https://www.osti.gov/servlets/purl/1691539.
@article{osti_1691539,
title = {Structural determinants of protocadherin-15 mechanics and function in hearing and balance perception},
author = {Choudhary, Deepanshu and Narui, Yoshie and Neel, Brandon L. and Wimalasena, Lahiru N. and Klanseck, Carissa F. and De-la-Torre, Pedro and Chen, Conghui and Araya-Secchi, Raul and Tamilselvan, Elakkiya and Sotomayor, Marcos},
abstractNote = {The vertebrate inner ear, responsible for hearing and balance, is able to sense minute mechanical stimuli originating from an extraordinarily broad range of sound frequencies and intensities or from head movements. Integral to these processes is the tip-link protein complex, which conveys force to open the inner-ear transduction channels that mediate sensory perception. Protocadherin-15 and cadherin-23, two atypically large cadherins with 11 and 27 extracellular cadherin (EC) repeats, are involved in deafness and balance disorders and assemble as parallel homodimers that interact to form the tip link. Here we report the X-ray crystal structure of a protocadherin-15 + cadherin-23 heterotetrameric complex at 2.9-Å resolution, depicting a parallel homodimer of protocadherin-15 EC1-3 molecules forming an antiparallel complex with two cadherin-23 EC1-2 molecules. In addition, we report structures for 10 protocadherin-15 fragments used to build complete high-resolution models of the monomeric protocadherin-15 ectodomain. Molecular dynamics simulations and validated crystal contacts are used to propose models for the complete extracellular protocadherin-15 parallel homodimer and the tip-link bond. Steered molecular dynamics simulations of these models suggest conditions in which a structurally diverse and multimodal protocadherin-15 ectodomain can act as a stiff or soft gating spring. These results reveal the structural determinants of tip-link–mediated inner-ear sensory perception and elucidate protocadherin-15’s structural and adhesive properties relevant in disease.},
doi = {10.1073/pnas.1920444117},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 40,
volume = 117,
place = {United States},
year = {Tue Sep 22 00:00:00 EDT 2020},
month = {Tue Sep 22 00:00:00 EDT 2020}
}
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