Doctor of Philosophy, The Ohio State University, 2023, Biophysics

Cadherins are a family of large transmembrane glycoproteins instrumental in facilitating organ formation during morphogenesis in vertebrates and invertebrates. At the cellular level, they are involved in adhesion, signaling, recognition, mechanotransduction, and motility. In the modern classification of the cadherin superfamily, classical cadherins with five extracellular cadherin (EC) repeats as well as clustered and non-clustered -protocadherins with six or seven EC repeats have been well-studied and their homophilic/heterophilic interactions with molecules on the same (cis) cell or opposite (trans) cells have been characterized. Complexity arises when the number of EC repeats increases with diverse Ca2+ coordination at linker regions between two consecutive EC repeats. In larger cadherins, such as cadherin-23 (CDH23), protocadherin-15 (PCDH15) and cadherin epithelial growth factor (EGF) Laminin-G (LAG or LamG) seven pass G-type receptor-1 (CELSR1), the structural flexibility afforded by different Ca2+ coordination plays determinant roles in their adhesion capacity during inner-ear mechanotransduction and planar cell polarity (PCP). CDH23 and PCDH15, each with 27 and 11 EC repeats, connect two adjacent hair- like protrusions known as stereocilia together atop of a hair cell, the primary mechanosensory cell in the inner ear. Through heterophilic interactions between their first two N-terminal EC repeats, CDH23 and PCDH15 form a filament known as the tip link. In response to sound, stereocilia undergo displacement and the tip link experiences tension, which opens the ion-conducting mechanotransduction channels on the tip-link's lower end to send signals to the brain. The heterophilic trans tetrameric complex formed by CDH23 and PCDH15, and the cis interactions along the length of PCDH15 have been well-studied in the past but full-length ectodomain structures and high-resolution structural models of complete CDH23 and PCHD15 ectodomain have not been resolved. H (open full item for complete abstract)

Committee: Marcos Sotomayor (Advisor) Subjects: Biochemistry; Biophysics