Person:

Sotomayor, Marcos

Members of the cadherin superfamily of proteins are involved in diverse biological processes such as morphogenesis, sound transduction, and neuronal connectivity. Key to cadherin function is their extracellular domain containing cadherin repeats, which can mediate interactions involved in adhesion and cell signaling. Recent cellular, biochemical, and structural studies have revealed that physical interaction among cadherins is more complex than originally thought. Here we review work on new cadherin complexes and discuss how the classification of the mammalian family can be used to search for additional cadherin-interacting partners. We also highlight some of the challenges in cadherin research; namely, the characterization of a cadherin connectome in biochemical and structural terms, as well as the elucidation of molecular mechanisms underlying the functional diversity of nonclassical cadherins in vivo.

Tip links of the inner ear are protein filaments essential for hearing and balance. Two atypical cadherins, cadherin-23 and protocadherin-15, interact in a Ca2+-dependent manner to form tip links. The largely unknown structure and mechanics of these proteins are integral to understanding how tip links pull on ion channels to initiate sensory perception. Protocadherin-15 has 11 extracellular cadherin (EC) repeats. Its EC3-4 linker lacks several of the canonical Ca2+-binding residues, and contains an aspartate-to-alanine polymorphism (D414A) under positive selection in East Asian populations. We present structures of protocadherin-15 EC3-5 featuring two Ca2+-binding linker regions: canonical EC4-5 linker binding three Ca2+ ions, and non-canonical EC3-4 linker binding only two Ca2+ ions. Our structures and biochemical assays reveal little difference between the D414 and D414A variants. Simulations predict that the partial Ca2+-free EC3-4 linker exhibits increased flexural flexibility without compromised mechanical strength, providing insight into the dynamics of tip links and other atypical cadherins.