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Cited by 4Hearing, Cochlea, Tinnitus, GeneticsEvolution and Genetic DynamicsVestibular and auditory disorders

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Interpreting the Evolutionary Echoes of a Protein Complex Essential for Inner-Ear Mechanosensation

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Nisler, Collin R, Narui, Yoshie, Scheib, Emily, Choudhary, Deepanshu, Bowman, Jacob D, Mandayam Bharathi, Harsha, Lynch, Vincent J, Sotomayor, Marcos·2023·Molecular Biology and Evolution
DOI 10.1093/molbev/msad057PMC PMC10089651

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Abstract

The sensory epithelium of the inner ear, found in all extant lineages of vertebrates, has been subjected to over 500 million years of evolution, resulting in the complex inner ear of modern vertebrates. Inner-ear adaptations are as diverse as the species in which they are found, and such unique anatomical variations have been well studied. However, the evolutionary details of the molecular machinery that is required for hearing are less well known. Two molecules that are essential for hearing in vertebrates are cadherin-23 and protocadherin-15, proteins whose interaction with one another acts as the focal point of force transmission when converting sound waves into electrical signals that the brain can interpret. This "tip-link" interaction exists in every lineage of vertebrates, but little is known about the structure or mechanical properties of these proteins in most non-mammalian lineages. Here, we use various techniques to characterize the evolution of this protein interaction. Results show how evolutionary sequence changes in this complex affect its biophysical properties both in simulations and experiments, with variations in interaction strength and dynamics among extant vertebrate lineages. Evolutionary simulations also characterize how the biophysical properties of the complex in turn constrain its evolution and provide a possible explanation for the increase in deafness-causing mutants observed in cadherin-23 relative to protocadherin-15. Together, these results suggest a general picture of tip-link evolution in which selection acted to modify the tip-link interface, although subsequent neutral evolution combined with varying degrees of purifying selection drove additional diversification in modern tetrapods.

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Metadata

Authors
Nisler, C. R., Narui, Y., Scheib, E., Choudhary, D., Bowman, J. D., Mandayam Bharathi, H., Lynch, V. J., & Sotomayor, M.
Affiliations
  • The Ohio State University (US)
  • University at Buffalo, State University of New York (US)
  • Department of Chemistry and Biochemistry, The Ohio State University , 484 W 12th Avenue, Columbus, OH
Corresponding author
Sotomayor, Marcos
ORCID
Venue
Molecular Biology and Evolution
Publisher
Oxford University Press (OUP)
Published
2023-03-13
Volume
40
Issue
4
ISSN
  • 0737-4038 (ISSN-L)
  • 1537-1719
DOI
10.1093/molbev/msad057
PMC
PMC10089651
OpenAlex
W4324018750
Cited by
4
References
2
Citations by year
2026: 4
FWCI
0.74
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Biology and Evolution (publishedVersion, cc-by-nc)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • Ohio State University
  • National Institutes of Health
Topics
  • Life Sciences › Neuroscience › Sensory Systems › Hearing, Cochlea, Tinnitus, Genetics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
  • Life Sciences › Neuroscience › Neurology › Vestibular and auditory disorders
Keywords
tip links, CDH23, PCDH15, auditory system evolution, protein-protein interaction, evolutionary simulation, purifying selection, neutral evolution, sensory epithelium, tetrapods
MeSH terms
Protocadherins, Animals, Hearing, Ear, Inner, Cadherins

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