Molecular logic of neuronal self-recognition through protocadherin domain interactions.
Publication Type:Journal Article
Source:Cell, Volume 163, Issue 3, p.629-42 (2015)
Keywords:Amino Acid Sequence, Animals, Cadherins, Crystallography, X-Ray, Mice, Models, Molecular, Molecular Sequence Data, Nervous System Physiological Phenomena, Neurons, Protein Structure, Tertiary, Sequence Alignment
<p>Self-avoidance, a process preventing interactions of axons and dendrites from the same neuron during development, is mediated in vertebrates through the stochastic single-neuron expression of clustered protocadherin protein isoforms. Extracellular cadherin (EC) domains mediate isoform-specific homophilic binding between cells, conferring cell recognition through a poorly understood mechanism. Here, we report crystal structures for the EC1-EC3 domain regions from four protocadherin isoforms representing the α, β, and γ subfamilies. All are rod shaped and monomeric in solution. Biophysical measurements, cell aggregation assays, and computational docking reveal that trans binding between cells depends on the EC1-EC4 domains, which interact in an antiparallel orientation. We also show that the EC6 domains are required for the formation of cis-dimers. Overall, our results are consistent with a model in which protocadherin cis-dimers engage in a head-to-tail interaction between EC1-EC4 domains from apposed cell surfaces, possibly forming a zipper-like protein assembly, and thus providing a size-dependent self-recognition mechanism.</p>