Mammalian collagen IV

Abstract

Four decades have passed since the first discovery of collagen IV by Kefalides in 1966. Since then collagen IV has been investigated extensively by a large number of research laboratories around the world. Advances in molecular genetics have resulted in identification of six evolutionary related mammalian genes encoding six different polypeptide chains of collagen IV. The genes are differentially expressed during the embryonic development, providing different tissues with specific collagen IV networks each having unique biochemical properties. Newly translated alpha-chains interact and assemble in the endoplasmic reticulum in a chain-specific fashion and form unique heterotrimers. Unlike most collagens, type IV collagen is an exclusive member of the basement membranes and through a complex inter- and intramolecular interactions form supramolecular networks that influence cell adhesion, migration, and differentiation. Collagen IV is directly involved in a number of genetic and acquired disease such as Alport's and Goodpasture's syndromes. Recent discoveries have also highlighted a new and direct role for collagen IV in the development of rare genetic diseases such as cerebral hemorrhage and porencephaly in infants and hemorrhagic stroke in adults. Years of intensive investigations have resulted in a vast body of information about the structure, function, and biology of collagen IV. In this review article, we will summarize essential findings on the structural and functional relationships of different collagen IV chains and their roles in health and disease.

Fig. 1

Schematic view of gene localization, organization, gene product, and assembly of six different isoforms of human collagen IV chains. The genes, COL4A1/COL4A2 on chromosome 13 (A), COL4A3/COL4A4 on chromosome 2 (B), and COL4A5/COL4A6 on chromosome X (C), are organized in pair sitting head-to-head and separated by a short promoter region that both genes share. The paired genes are transcribed in a bidirectional fashion and translated into individual α-chains. Each chain starts with an N-terminal 7S domain having an N-linked oligosaccharide (Y-shaped and black), a long collagenous domain, and a C-terminal globular noncollagenous domain (NC1). Assembly of each heterotrimer with characteristic stoichiometry of chains initiates by chain-specific recognition of NC1 domains, formation of NC1-trimers followed by supercoiling of the triple-helical collagenous domains which proceeds toward the N-terminal 7S domains. Out of 56 potential heterotrimers, only three specific combinations: α1α1α2, α3α4α5, and α5α5α6, have been found in vivo.

Fig. 2

Generic network formation and structural features of the NC1 domain. A heterotrimeric collagen IV molecule (A) can interact through its N-terminal 7S domains to form a tetramer (left) or through its NC1 domains to form a dimer (right). Through complex interactions, these molecules can further interact to form higher order of supramolecular organization and three-dimensional networks. The networks are further enforced by supramolecular twisting and lateral associations of collagenous domains (arrow heads). Domain organization and configuration of the NC1 domains in hexamer and trimer (B). The NC1 hexamer is formed by end-to-end interaction of two NC1 trimers. Relative location of two immunologically reactive epitopes, EA (yellow) and EB (orange) on the alpha3(IV) NC1 domain are shown. Each NC1 trimer is stabilized by a three-dimensional domain swapping mechanism through tight and selective interactions between two sites comprising a beta-hairpin motif and its docking site with a variable region (VR3).

Fig. 3

Location of integrin-binding sites within three different collagen IV heterotrimers. Binding sites within the triple-helical cyanogen bromide-derived fragment (CB3) and specific NC1 domains are indicated.