(A) Comparison of chicken ZP3 (Protein Data Bank: 3NK4) and human uromodulin
(4WRN). Independent alignment of the ZP-N and ZP-C domain reveal close
structural similarity of ~3.4 Å and 4.2 Å rmsd, respectively.
When viewed together (and aligned based on the ZP-N domain), however, there is
no similarity in the positioning of ZP-C relative to ZP-N (adapted from Bokhove et al., 2016). (B) Several classical
“ZP domain”-containing proteins often contain N-terminal repeats
of the ZP-N domain. Structural databases such as Pfam and the Conserved Domain
Database (CDD), however, do not detect these additional repeats in human ZP
proteins; Pfam also did not detect the conserved trefoil domain in ZP1. The most
extreme case of this ZP-N duplication is in abalone VERL, which has 22 ZP-N
repeats with different modes of evolution based on genetic effects and
adaptation with coevolving sperm proteins. Pfam includes an additional entry for
78 residues of the VERL repeats (pfam11386), but this annotation does not fully
span the repeats or report ZP-N homology. The C-terminal ZP module of VERL is
also not detected in either database (adapted from Wilburn and Swanson, 2016).