Structural determinants of cadherin-23 function in hearing and deafness

Area of Science:

• Biochemistry
• Structural Biology
• Genetics

Background:

• The hair-cell tip link is essential for hearing, connecting to mechanosensitive channels.
• It is composed of protocadherin-15 and cadherin-23; mutations in these proteins cause deafness.
• The molecular structure and mechanics of cadherin-23 and its role in deafness are poorly understood.

Purpose of the Study:

• To determine the molecular structure of cadherin-23 repeats.
• To investigate the impact of deafness-associated mutations on cadherin-23 structure and function.
• To elucidate the mechanisms underlying inherited deafness related to tip link proteins.

Main Methods:

• X-ray crystallography was used to obtain crystal structures of cadherin-23 extracellular repeats.
• Molecular dynamics simulations were performed to assess the protein's mechanical properties.
• Analysis of mutation effects on calcium binding affinity and protein rigidity.

Main Results:

• Crystal structures revealed typical cadherin folds with an elongated N terminus and a Ca(2+)-binding site.
• The deafness mutation D101G introduces a bend between repeats and reduces Ca(2+) affinity.
• Simulations indicated cadherin-23 repeats are stiff, and Ca(2+) binding enhances rigidity and unfolding strength.

Conclusions:

• The study defines a new cadherin family and provides structural insights into cadherin-23.
• Findings suggest mechanisms for inherited deafness by linking structural defects to impaired tip link function.
• The results offer a basis for understanding cadherin-23 interactions within the tip link complex.