This book presents an overview of the entire field of cadherin research and provides the current basic concept of cadherins. Cadherins have been widely accepted as key regulators of animal development and physiological functions, and it also has become clear that they play essential roles in various human diseases. With contributions by leading scientists, the book covers various aspects of the cadherin superfamily including the history of cadherin research, basic properties of classical cadherins as well as non-classical cadherins, cadherin-associated proteins, and the roles of cadherins in health and diseases. In addition, the book presents some contradictory results and important unanswered questions, and the authors propose their working hypotheses or future directions, to inspire future studies. This volume enables graduate students and young researchers to learn the basics and gain a comprehensive image of the cadherin superfamily, and experts in the field will easily find various topics of interest in relevant areas of study. Additionally, a list of cadherin-related diseases is included for quick reference to cadherins in human diseases.

Development and functionality of multicellular organisms relies on precise and strong adhesion between cells. Members of the cadherin superfamily of proteins are involved in calcium-dependent cell-cell adhesion in animals and have been shown to play vital roles in various relevant biological processes. The cadherin superfamily can be largely classified into three subfamilies: the classical cadherins, the non-clustered protocadherins, and the clustered protocadherins. The typical cadherin protein consists of a single-pass transmembrane domain, a cytoplasmic domain, and multiple non-identical extracellular cadherin (EC) repeats. These ECs are defined by their Greek-key fold and an EC linker region with highly conserved calcium-binding sites. The binding of calcium helps to provide the rigidity necessary for proper protein-protein interaction. Within this work I focus on cadherins responsible for mechanotransduction, both from the classical and non-clustered subfamilies. Adherens junctions are formed by classical members of the cadherin superfamily and provide strong adhesion between cells. Past experiments have determined that interactions between individual cadherins are weak and therefore the strength provided by epithelial cadherin (CDH1), the major cadherin of adherens junctions, must come about through the formation of cadherin complexes. These cadherin complexes are composed of multiple CDH1 molecules binding through trans- (ectodomains originating from adjacent cells) and cis-interactions (ectodomains originating from the same cell) as seen in x-ray crystal structures and cryo-electron tomography images. While most experiments have focused on single homodimers, the mechanical unbinding events of cadherin junctional complexes and their effect on the membrane and associated cytoplasmic proteins remains unexplored. My work on CDH1 junctional complexes and their associated proteins utilizes large-scale all-atom molecular dynamics (MD) simulations to probe the adherens junction’s response to mechanical force at the molecular level. In collaboration with other group members, we found that ectodomain dimers of classical members of the cadherin superfamily have a distinct two-phased elastic response to force that might facilitate enhanced flexibility to preserve cellular adhesion during mild mechanical stress. Conversely, we found that clustered protocadherins, responsible for neuronal self-recognition, form brittle ectodomain dimers that are capable of forming numerous transient intermediates with implications for binding specificity. When these cadherin ectodomain systems were simulated as junctional complexes, we found that the classical cadherins can act as molecular shock absorbers with complex mechanical responses influenced by cis contacts and that the clustered protocadherin-mediated junction remains brittle. Finally, simulations of a minimal adherens junction, which includes the CDH1 transmembrane and cytoplasmic domains and associated binding partners, show that force originating from an external source on CDH1 has implications on the predicted order of junctional disassembly upon strenuous mechanical stress. In parallel, I worked with a non-clustered protocadherin essential for hearing. Within the inner ear of vertebrates, hair-cells mediate sound, balance, and acceleration perception through the mechanotransduction of force by tip-link filaments. These tip links are composed of cadherin-23 and protocadherin-15 (PCDH15), two atypical non-clustered protocadherins that form a calcium-dependent heterotetramer. The structure of these cadherins and the mechanism behind their mechanotransduction leaves much to be explored. To better discern the first steps behind inner-ear mechanotransduction multiple crystal structures of PCDH15 were solved, the entire ectodomain of PCDH15 was modeled, and all-atom MD simulations were performed that helped to inform our view of PCDH15’s multimodal elastic response. Overall, our studies provided insight into the mechanics of the classical, clustered, and non-clustered cadherins. This work details the mechanical response of single cadherin dimers, multi-protein cadherin-mediated junctions, a minimal cadherin junction with internal and external components, and a mechanotransducing cadherin complex. Our simulations contribute to the atomistic description of these complexes and provides insights into the function of cadherin-mediated junctions and links with testable predictions concerning their elastic and mechanical properties.

"Yet another cell and molecular biology book? At the very least, you would think that if I was going to write a textbook, I should write one in an area that really needs one instead of a subject that already has multiple excellent and definitive books. So, why write this book, then? First, it's a course that I have enjoyed teaching for many years, so I am very familiar with what a student really needs to take away from this class within the time constraints of a semester. Second, because it is a course that many students take, there is a greater opportunity to make an impact on more students' pocketbooks than if I were to start off writing a book for a highly specialized upper- level course. And finally, it was fun to research and write, and can be revised easily for inclusion as part of our next textbook, High School Biology."--Open Textbook Library.

This book provides an overview of the main topics of current cell adhesion research including structural analyses of cell adhesion molecules and studies to their functional role in vitro and in vivo. The present volume focuses on the four major families of cell-adhesion receptors, i.e. the cadherins, the integrins, the Ig-superfamily and the selectin-based adhesion system which are discussed in detail by numerous experts in the field.