Abstract
Protocadherins (Pcdhs) are cell adhesion and signaling proteins used by neurons to develop and maintain neuronal networks, relying on trans homophilic interactions between their extracellular cadherin (EC) repeat domains. We present the structure of the antiparallel EC1-4 homodimer of human PcdhγB3, a member of the γ subfamily of clustered Pcdhs. Structure and sequence comparisons of α, β, and γ clustered Pcdh isoforms illustrate that subfamilies encode specificity in distinct ways through diversification of loop region structure and composition in EC2 and EC3, which contains isoform-specific conservation of primarily polar residues. In contrast, the EC1/EC4 interface comprises hydrophobic interactions that provide non-selective dimerization affinity. Using sequence coevolution analysis, we found evidence for a similar antiparallel EC1-4 interaction in non-clustered Pcdh families. We thus deduce that the EC1-4 antiparallel homodimer is a general interaction strategy that evolved before the divergence of these distinct protocadherin families.
Highlights
Protocadherins (Pcdhs) encompass about 70% of the cadherin superfamily in mammals, and are involved in cell adhesion in the nervous system of higher animals (Hulpiau and van Roy, 2011; Hulpiau et al, 2013; Keeler et al, 2015; Sotomayor et al, 2014)
EC4 has a unique b-strand arrangement compared to EC1-EC3 (Figure 1B,C) and all known cadherin repeat structures
We and others predicted that clustered Pcdhs form homophilic antiparallel EC1-EC4 complexes based on crystal structures, mutagenesis and bioinformatics (Nicoludis et al, 2015; Rubinstein et al, 2015)
Summary
Protocadherins (Pcdhs) encompass about 70% of the cadherin superfamily in mammals, and are involved in cell adhesion in the nervous system of higher animals (Hulpiau and van Roy, 2011; Hulpiau et al, 2013; Keeler et al, 2015; Sotomayor et al, 2014). Pcdh is involved in germ layer differentiation (Rashid et al, 2006; Yoshida, 2003), and Pcdh and Pcdh mediate cell sorting and migration during gastrulation (Kim et al, 1998; Kuroda et al, 2002). Both clustered and non-clustered Pcdhs control these phenotypes through homophilic interactions of their extracellular cadherin (EC) repeat domains
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