Resolving The Mechanism Of Adhesion Mediated By A Non-Clustered Delta-1 Protocadherin

Cadherins form a large family of calcium-dependent cell adhesion proteins involved in cell differentiation, tissue morphogenesis and neuronal connectivity. Non-clustered delta-protocadherins are a subgroup of cadherins with 6 or 7 extracellular cadherin (EC) repeats and cytoplasmic domains distinct from classical cadherins. These proteins mediate homophilic adhesion and have been implicated in various diseases, including asthma, autism, epilepsy and cancer. However, how delta-1 protocadherins use their extracellular domain to mediate adhesion is unknown. Here we present the first X-ray crystal structures of a delta1-protocadherin member (Protocadherin-1) involved in asthma. Protocadherin-1 (PCDH1) is a delta-1 protocadherin expressed mainly in the airway epithelium, skin keratinocytes, and lungs. The structure revealed binding modes that involve antiparallel overlap of multiple EC repeats. Mutagenesis, binding assays and other biochemical experiments validated the modes of adhesion as predicted from these structures. Overall, our studies reveal the molecular mechanism of adhesion mediated by PCDH1 and shed light on its role in maintaining epithelial integrity, the loss of which causes asthma.