Structure of the N Terminus of Cadherin 23 Reveals a New Adhesion Mechanism for a Subset of Cadherin Superfamily Members

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2010 May 26

PMID 20498078

Citations 32

Authors

Heather M Elledge

Piotr Kazmierczak

Peter Clark

Jeremiah S Joseph

Anand Kolatkar

Peter Kuhn

Ulrich Muller

Affiliations

Soon will be listed here.

Abstract

The cadherin superfamily encodes more than 100 receptors with diverse functions in tissue development and homeostasis. Classical cadherins mediate adhesion by binding interactions that depend on their N-terminal extracellular cadherin (EC) domains, which swap N-terminal beta-strands. Sequence alignments suggest that the strand-swap binding mode is not commonly used by functionally divergent cadherins. Here, we have determined the structure of the EC1-EC2 domains of cadherin 23 (CDH23), which binds to protocadherin 15 (PCDH15) to form tip links of mechanosensory hair cells. Unlike classical cadherins, the CDH23 N terminus contains polar amino acids that bind Ca(2+). The N terminus of PCDH15 also contains polar amino acids. Mutations in polar amino acids within EC1 of CDH23 and PCDH15 abolish interaction between the two cadherins. PCDH21 and PCDH24 contain similarly charged N termini, suggesting that a subset of cadherins share a common interaction mechanism that differs from the strand-swap binding mode of classical cadherins.

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References

Sakaguchi H, Tokita J, Muller U, Kachar B . Tip links in hair cells: molecular composition and role in hearing loss. Curr Opin Otolaryngol Head Neck Surg. 2009; 17(5):388-93. PMC: 2921850. DOI: 10.1097/MOO.0b013e3283303472. View

Kazmierczak P, Sakaguchi H, Tokita J, Wilson-Kubalek E, Milligan R, Muller U . Cadherin 23 and protocadherin 15 interact to form tip-link filaments in sensory hair cells. Nature. 2007; 449(7158):87-91. DOI: 10.1038/nature06091. View

Alagramam K, Murcia C, Kwon H, Pawlowski K, Wright C, Woychik R . The mouse Ames waltzer hearing-loss mutant is caused by mutation of Pcdh15, a novel protocadherin gene. Nat Genet. 2001; 27(1):99-102. DOI: 10.1038/83837. View

BOSHER S, Warren R . Very low calcium content of cochlear endolymph, an extracellular fluid. Nature. 1978; 273(5661):377-8. DOI: 10.1038/273377a0. View

Boggon T, Murray J, Wong E, Gumbiner B, Shapiro L . C-cadherin ectodomain structure and implications for cell adhesion mechanisms. Science. 2002; 296(5571):1308-13. DOI: 10.1126/science.1071559. View

Suzuki S, Takeichi M . Cadherins in neuronal morphogenesis and function. Dev Growth Differ. 2008; 50 Suppl 1:S119-30. DOI: 10.1111/j.1440-169X.2008.01002.x. View

Ahmed Z, Bernstein S, Ahmed Z, Khan S, Griffith A, Morell R . Mutations of the protocadherin gene PCDH15 cause Usher syndrome type 1F. Am J Hum Genet. 2001; 69(1):25-34. PMC: 1226045. DOI: 10.1086/321277. View

Bork J, Peters L, Bernstein S, Ahmed Z, Ness S, Polomeno R . Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene CDH23. Am J Hum Genet. 2000; 68(1):26-37. PMC: 1234923. DOI: 10.1086/316954. View

Ciatto C, Bahna F, Zampieri N, VanSteenhouse H, Katsamba P, Ahlsen G . T-cadherin structures reveal a novel adhesive binding mechanism. Nat Struct Mol Biol. 2010; 17(3):339-47. PMC: 2873897. DOI: 10.1038/nsmb.1781. View

10.

Harrison O, Bahna F, Katsamba P, Jin X, Brasch J, Vendome J . Two-step adhesive binding by classical cadherins. Nat Struct Mol Biol. 2010; 17(3):348-57. PMC: 2872554. DOI: 10.1038/nsmb.1784. View

11.

Bolz H, Ebermann I, Gal A . Protocadherin-21 (PCDH21), a candidate gene for human retinal dystrophies. Mol Vis. 2005; 11:929-33. View

12.

. The CCP4 suite: programs for protein crystallography. Acta Crystallogr D Biol Crystallogr. 1994; 50(Pt 5):760-3. DOI: 10.1107/S0907444994003112. View

13.

Chen C, Posy S, Ben-Shaul A, Shapiro L, Honig B . Specificity of cell-cell adhesion by classical cadherins: Critical role for low-affinity dimerization through beta-strand swapping. Proc Natl Acad Sci U S A. 2005; 102(24):8531-6. PMC: 1150851. DOI: 10.1073/pnas.0503319102. View

14.

Patel S, Ciatto C, Chen C, Bahna F, Rajebhosale M, Arkus N . Type II cadherin ectodomain structures: implications for classical cadherin specificity. Cell. 2006; 124(6):1255-68. DOI: 10.1016/j.cell.2005.12.046. View

15.

Alagramam K, Yuan H, Kuehn M, Murcia C, Wayne S, Srisailpathy C . Mutations in the novel protocadherin PCDH15 cause Usher syndrome type 1F. Hum Mol Genet. 2001; 10(16):1709-18. DOI: 10.1093/hmg/10.16.1709. View

16.

Terwilliger T . SOLVE and RESOLVE: automated structure solution, density modification and model building. J Synchrotron Radiat. 2003; 11(Pt 1):49-52. DOI: 10.1107/s0909049503023938. View

17.

Bolz H, von Brederlow B, Ramirez A, Bryda E, Kutsche K, Nothwang H . Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D. Nat Genet. 2001; 27(1):108-12. DOI: 10.1038/83667. View

18.

Shapiro L, Fannon A, Kwong P, Thompson A, Lehmann M, Grubel G . Structural basis of cell-cell adhesion by cadherins. Nature. 1995; 374(6520):327-37. DOI: 10.1038/374327a0. View

19.

Muller U . Cadherins and mechanotransduction by hair cells. Curr Opin Cell Biol. 2008; 20(5):557-66. PMC: 2692626. DOI: 10.1016/j.ceb.2008.06.004. View

20.

Otwinowski Z, Minor W . Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 1997; 276:307-26. DOI: 10.1016/S0076-6879(97)76066-X. View