The hearing-essential intracellular domain of PCDH15 reveals a new layer of auditory mechanotransduction
Year: 2026
Type: preprint
Abstract: 1 Abstract 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.
Institutions: University of Antwerp, Lund University, Science for Life Laboratory, European Molecular Biology Laboratory, European Molecular Biology Laboratory, Centre National de la Recherche Scientifique, Inserm, Institut Pasteur, Collège de France, Université Paris Cité, Assistance Publique – Hôpitaux de Paris, Fondation Pour l'Audition, Institut de l'Audition
Language: English
Subfield: Sensory Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7213636629