Zona pellucida-like domain

The zona pellucida-like domain (ZP domain / ZP-like domain / ZP module)^[1][2] is a large protein region of about 260 amino acids. It has been recognised in a variety of receptor-like eukaryotic glycoproteins.^[1] All of these molecules are mosaic proteins with a large extracellular region composed of various domains, often followed by either a transmembrane domain and a short cytoplasmic region or by a GPI-anchor.^[2]

Functional and crystallographic studies revealed that the "ZP domain" region common to all these proteins is a protein polymerization module that consists of two distinct but structurally related immunoglobulin-like domains, ZP-N and ZP-C, separated by an interdomain linker (ITD).^{[3][4][5][6][7][8][9]} The ZP module is located in the C-terminal portion of the extracellular region and – with the exception of non-polymeric family member ENG^[10] – contains 8 or 10 conserved Cys residues involved in disulfide bonds.^[4][5][8] The ZP-C domain contains a EHP/IHP motif that controls polymerization.^[11]

The first 3D structure of a homopolymeric ZP module protein filament, native human uromodulin (UMOD), was determined by cryo-EM.^[12][13]

Additional copies of isolated ZP-N domains are found in the N-terminal region of egg coat protein subunits involved in fertilization in both vertebrates and invertebrates, with the human zona pellucida components ZP1, ZP2 and ZP4 being the best understood.^[4][14] The mollusc "vitelline envelope receptor for egg lysin" (VERL, Q8WR62) is found in the vitelline envelope of mollusc eggs and consists of 22 VERL repeats followed by a ZP module. Structural work from 2017 demonstrated that VERL repeats are also ZP-N domains.^[15]