Collagen IV Exploits a Cl- Step Gradient for Scaffold Assembly.

Collagen molecules are crucial extracellular players in animal tissue development and in functions ranging from ultrafiltration to organism locomotion. Among the 28 types of collagen found in human, type IV collagen stands out as a primordial type found in all species of the animal kingdom. Collagen IV forms smart scaffolds for basement membranes, sheet-like acellular structures that isolate, coordinate, and direct cells during morphogenesis. Collagen IV is also involved in multiple functions in developed tissues. As part of the basement membrane, collagen IV scaffolds provide mechanical strength, spatially tether extracellular macromolecules and directly signal to cells via receptor binding sites. Proper assembly and structure of the scaffolds are critical for development and function of multiple types of basement membranes. Within last 5 years it was established that Cl- concentration is a key factor for initiating collagen IV scaffold assembly. The biological role of Cl- in multiple physiological processes and detailed mechanisms for its signaling and structural impacts are well established. Cl- gradients are generated across the plasma and intracellular organelle membranes. As collagen IV molecules are secreted outside the cell, they experience a switch from low to high Cl- concentration. This transition works as a trigger for collagen IV scaffold assembly. Within the scaffold, collagen IV remains to be a Cl- sensor as its structural integrity continues to depend on Cl- concentration. Here, we review recent findings and set future directions for studies on the role of Cl- in type IV collagen assembly, function, and disease.