Identification of unique α4 chain structure and conserved antiangiogenic activity of α3NC1 type IV collagen in zebrafish

Background: Type IV collagen is an abundant component of basement membranes in all multicellular species and is essential for the extracellular scaffold supporting tissue architecture and function. Lower organisms typically have two type IV collagen genes, encoding a1 and a2 chains, in contrast with the six genes in humans, encoding a1-a6 chains. The a chains assemble into trimeric protomers, the building blocks of the type IV collagen network. The detailed evolutionary conservation of type IV collagen network remains to be studied.Results: We report on the molecular evolution of type IV collagen genes. The zebrafish a4 non-collagenous (NC1) domain, in contrast with its human ortholog, contains an additional cysteine residue and lacks the M93 and K211 residues involved in sulfilimine bond formation between adjacent protomers. This may alter a4 chain interactions with other a chains, as supported by temporal and anatomic expression patterns of collagen IV chains during the zebrafish development. Despite the divergence between zebrafish and human a3 NC1 domain (endogenous angiogenesis inhibitor, Tumstatin), the zebrafish a3 NC1 domain exhibits conserved antiangiogenic activity in human endothelial cells.Conclusions: work supports type IV collagen is largely conserved between zebrafish and humans, with a possible difference involving the a4 chain.

Automated summary

This study reports on the molecular evolution of type IV collagen genes, finding that the zebrafish a4 non-collagenous (NC1) domain has a cysteine residue and lacks certain residues involved in bond formation between adjacent protomers, potentially affecting its interactions with other chains. The zebrafish a3 NC1 domain exhibits conserved antiangiogenic activity in human endothelial cells despite differences between zebrafish and human versions.