TY - JOUR
T1 - Molecular Logic of Neuronal Self-Recognition through Protocadherin Domain Interactions
AU - Rubinstein, Rotem
AU - Thu, Chan Aye
AU - Goodman, Kerry Marie
AU - Wolcott, Holly Noelle
AU - Bahna, Fabiana
AU - Mannepalli, Seetha
AU - Ahlsen, Goran
AU - Chevee, Maxime
AU - Halim, Adnan
AU - Clausen, Henrik
AU - Maniatis, Tom
AU - Shapiro, Lawrence
AU - Honig, Barry
N1 - Copyright © 2015 Elsevier Inc. All rights reserved.
PY - 2015/10/22
Y1 - 2015/10/22
N2 - 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.
AB - 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.
U2 - 10.1016/j.cell.2015.09.026
DO - 10.1016/j.cell.2015.09.026
M3 - Journal article
C2 - 26478182
SN - 0092-8674
VL - 163
SP - 629
EP - 642
JO - Cell
JF - Cell
IS - 3
ER -