Knowledge Bank

Cadherins form a large superfamily of proteins involved in cell adhesion, development, and cancer. Although classical cadherins have been studied extensively, we know little about non-classical cadherins. Cadherin-23 (cdh23) is a non-classical cadherin essential for hearing. It forms a bridging structure called the tip-link, and mutations in the extracellular cadherin (EC) repeats of cdh23 have been shown to cause hereditary deafness, although the mechanism by which many of these missense mutations affect the tip-link is unknown. The integrity of the tip-link and of cdh23 requires the presence of calcium, and simulations of the cdh23 have shown that the mechanical strength is altered by decreased calcium-binding affinity. However, these simulations were performed using a non-polarizable force field. In this thesis, I employed biochemical techniques to determine the stability of mutant and wild-type form of cdh23 fragments to develop an understanding of the mechanism behind deafness mutations. In addition, I performed steered molecular dynamics simulations of cdh23 repeats with the Drude polarizable force field, which could determine the role of cdh23 in hearing as either a stiff cable or an elastic element, and further our understanding of non-classical cadherins.