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The Journal of Neuroscience, October 29, 2008, 28(44):11269-11276; doi:10.1523/JNEUROSCI.3833-08.2008

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Cellular/Molecular
MAGI-1, A Candidate Stereociliary Scaffolding Protein, Associates with the Tip-Link Component Cadherin 23

Zhigang Xu,¹ Anthony W. Peng,^1,2 Kazuo Oshima,¹ and Stefan Heller¹

¹Departments of Otolaryngology—Head and Neck Surgery and Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, and ²Program in Health Sciences and Technology—Speech and Hearing Bioscience and Technology, Harvard–Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

Correspondence should be addressed to Dr. Stefan Heller, 801 Welch Road, Stanford, CA 94305. Email: hellers{at}stanford.edu

Inner ear hair-cell mechanoelectrical transduction is mediated by a largely unidentified multiprotein complex associated with the stereociliary tips of hair bundles. One identified component of tip links, which are the extracellular filamentous connectors implicated in gating the mechanoelectrical transduction channels, is the transmembrane protein cadherin 23 (Cdh23), more specifically, the hair- cell-specific Cdh23(+68) splice variant. Using the intracellular domain of Cdh23(+68) as bait, we identified in a cochlear cDNA library MAGI-1, a MAGUK (membrane-associated guanylate kinase) protein. MAGI-1 binds via its PDZ4 domain to a C-terminal PDZ-binding site on Cdh23. MAGI-1 immunoreactivity was detectable throughout neonatal stereocilia in a distribution similar to that of Cdh23. As development proceeded, MAGI-1 occurred in a punctate staining pattern on stereocilia, which was maintained into adulthood. Previous reports suggest that Cdh23 interacts via an internal PDZ-binding site with the PDZ1 domain of the stereociliary protein harmonin, and potentially via a weaker binding of its C terminus with harmonin's PDZ2 domain. We propose that MAGI-1 has the ability to replace harmonin's PDZ2 binding at Cdh23's C terminus. Moreover, the strong interaction between PDZ1 of harmonin and Cdh23 is interrupted by a 35 aa insertion in the hair-cell-specific Cdh23(+68) splice variant, which puts forward MAGI-1 as an attractive candidate for an intracellular scaffolding partner of this tip-link protein. Our results consequently support a role of MAGI-1 in the tip-link complex, where it could provide a sturdy connection with the cytoskeleton and with other components of the mechanoelectrical transduction complex.

Key words: cochlea; hair cell; inner ear; mechanotransduction; protocadherin 15; Usher syndrome

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Received Aug. 12, 2008; revised Sept. 21, 2008; accepted Sept. 24, 2008.

Correspondence should be addressed to Dr. Stefan Heller, 801 Welch Road, Stanford, CA 94305. Email: hellers{at}stanford.edu

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