Abstract
Stochastic cell-surface expression of α-, β-, and γ-clustered protocadherins (Pcdhs) provides vertebrate neurons with single-cell identities that underlie neuronal self-recognition. Here we report crystal structures of ectodomain fragments comprising cell-cell recognition regions of mouse γ-Pcdhs γA1, γA8, γB2, and γB7 revealing trans-homodimers, and of C-terminal ectodomain fragments from γ-Pcdhs γA4 and γB2, which depict cis-interacting regions in monomeric form. Together these structures span the entire γ-Pcdh ectodomain. The trans-dimer structures reveal determinants of γ-Pcdh isoform-specific homophilic recognition. We identified and structurally mapped cis-dimerization mutations to the C-terminal ectodomain structures. Biophysical studies showed that Pcdh ectodomains from γB-subfamily isoforms formed cis dimers, whereas γA isoforms did not, but both γA and γB isoforms could interact in cis with α-Pcdhs. Together, these data show how interaction specificity is distributed over all domains of the γ-Pcdh trans interface, and suggest that subfamily- or isoform-specific cis-interactions may play a role in the Pcdh-mediated neuronal self-recognition code.
Highlights
A characteristic of neural circuit assembly is that dendrites and axonal arbors of the same neuron do not stably contact one another, but are free to interact with the processes of other neurons (Zipursky and Grueber, 2013; Zipursky and Sanes, 2010)
We previously reported analytical ultracentrifugation (AUC) data showing that gB6, aC2, and gC5 Pcdh EC1–6 fragments exist as dimers-of-dimers in solution, mediated by an EC1–4 interface and a distinct extracellular cadherin domain 6 (EC6)-dependent interface (Rubinstein et al, 2015)
The structures of representative gA- and gB-Pcdh protein isoforms reported here complete a set of representative structures for trans-recognition interfaces from alternate clustered Pcdh isoforms, with structures available for at least two Pcdhs from each of the a, b- (Goodman et al, 2016), gB- (Nicoludis et al, 2016; this paper), and gA- Pcdh subfamilies
Summary
A characteristic of neural circuit assembly is that dendrites and axonal arbors of the same neuron do not stably contact one another, but are free to interact with the processes of other neurons (Zipursky and Grueber, 2013; Zipursky and Sanes, 2010) This fundamental property of neural circuit assembly is accomplished through a mechanism that mediates ‘self-avoidance’ between sister branches from individual neurons, while permitting interactions between non-self neurons. In both vertebrates and invertebrates, self-avoidance is thought to require the generation of unique single cell surface identities through mechanisms that involve the stochastic expression of unique combinations of cell surface protein isoforms (Zipursky and Grueber, 2013; Chen and Maniatis, 2013).
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