Molecular Logic of Neuronal Self-Recognition through Protocadherin Domain Interactions
Research output: Contribution to journal › Journal article › Research › peer-review
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.
Original language | English |
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Journal | Cell |
Volume | 163 |
Issue number | 3 |
Pages (from-to) | 629-42 |
Number of pages | 14 |
ISSN | 0092-8674 |
DOIs | |
Publication status | Published - 22 Oct 2015 |
ID: 151491932