The hearing-essential intracellular domain of PCDH15 reveals a new layer of auditory mechanotransduction

Current models of mechanotransduction in inner-ear hair cells explain how force is transmitted through the extracellular tip link but provide little insight into how force is propagated beneath the plasma membrane. Although the CD2 isoform of PCDH15 has been shown to be essential for hearing in mature mammalian hair cells, its structural and mechanical properties have remained largely unknown. Here, we combine computational sequence analysis, orthogonal biophysical characterization and small-angle X-ray scattering (SAXS) to show that the hearing-essential CD2 intracellular domain is an intrinsically disordered region (IDR) that behaves as a highly expanded acidic polyampholyte. CD2 remains predominantly monomeric in solution and occupies a larger conformational space at physiological-like ionic strength, whereas inclusion of the isoform-shared common region increases self-association. CD2 also contains a conserved regulatory interaction platform, providing a potential link between its polymer properties and cellular regulation. Together, these findings identify the CD2 intracellular domain as a polymer with biophysical properties consistent with a mechanically responsive structural element. Furthermore, they provide a framework for investigating how intracellular polymer mechanics may contribute to force transmission and adaptation in auditory mechanotransduction.