Resolving the mechanism of adhesion mediated by Protocadherin-1, a non-clustered delta-1 protocadherin
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Date
2018-03
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Abstract
Cadherins form a large family of calcium-dependent cell adhesion proteins involved in cell differentiation, tissue morphogenesis and neuronal connectivity. Non-clustered δ1-protocadherins form a cadherin subgroup with seven extracellular cadherin (EC) repeats and cytoplasmic domains distinct from classical cadherins. The non-clustered δ1 proteins mediate homophilic adhesion and have been implicated in various diseases including asthma, autism, Alzheimer's and cancer. However, how δ1-protocadherins use their extracellular domain to mediate adhesion is unknown. Here we present the first X-ray crystal structure of a δ1-protocadherin member (Protocadherin-1) involved in asthma. Protocadherin-1 (PCDH1) is a δ1-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 tested the modes of adhesion as predicted from the structure. Overall, our studies reveal the molecular mechanism of adhesion mediated by PCDH1EC1-4 and shed light on its role in maintaining epithelial integrity, the loss of which causes asthma. Further, this mode of adhesion is relevant for other δ1-protocadherins too as they are highly similar in sequence.
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Biological Sciences: 1st Place (The Ohio State University Edward F. Hayes Graduate Research Forum)
Keywords
adhesion, calcium-binding protein, asthma