RT Journal Article
SR Electronic
T1 Antiparallel protocadherin homodimers use distinct affinity- and specificity-mediating regions in cadherin repeats 1-4
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 063289
DO 10.1101/063289
A1 John M. Nicoludis
A1 Bennett E. Vogt
A1 Anna G. Green
A1 Charlotta P. I. Schärfe
A1 Debora S. Marks
A1 Rachelle Gaudet
YR 2016
UL http://biorxiv.org/content/early/2016/07/12/063289.abstract
AB 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 PcdhYB3, 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.