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Publication Abstract from PubMed

Collagen IV scaffold is a principal component of the basement membrane (BM), a specialized extracellular matrix that is essential for animal multicellularity and tissue evolution. Scaffold assembly begins with the trimerization of alpha-chains into protomers inside the cell, which then are secreted and undergo oligomerization outside the cell. For the ubiquitous scaffold composed of alpha1 and alpha2 chains, both intracellular and extracellular stages are mediated by the non-collagenous domain (NC1). The association of protomers is chloride-dependent, whereby chloride ions induce interactions of protomers' trimeric NC1 domains leading to NC1 hexamer formation. Here, we investigated the mechanisms, kinetics, and functionality of the chloride ion-mediated protomer assembly by using a single-chain technology to produce a stable NC1 trimer comprising alpha1, alpha2, and alpha1 NC1 monomers. We observed that in the presence of chloride, the single-chain NC1 trimer self-assembles into a hexamer, for which the crystal structure was determined. We discovered that a chloride ring, comprising twelve ions, induces the assembly of and stabilizes the NC1 hexamer. Furthermore, we found that the chloride ring is evolutionarily conserved across all animals, first appearing in cnidarians. These findings reveal a fundamental role for the chloride ring in the assembly of collagen IV scaffolds of BMs, a critical event enabling tissue evolution and development. Moreover, the single-chain technology is foundational for generating trimeric NC1 domains of other alpha-chain compositions to investigate the alpha121, alpha345, and alpha565 collagen IV scaffolds and to develop therapies for managing Alport syndrome, Goodpasture's disease, and cancerous tumor growth.

A chloride ring is an ancient evolutionary innovation mediating the assembly of the collagen IV scaffold of basement membranes.,Pedchenko V, Bauer R, Pokidysheva EN, Al-Shaer A, Forde NR, Fidler AL, Hudson BG, Boudko SP J Biol Chem. 2019 Mar 28. pii: RA119.007426. doi: 10.1074/jbc.RA119.007426. PMID:30923125^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.