Molecular Diversity of Basement Membrane Collagen: Elucidation of the Goodpasture's Epitope

Abstract

Basement membranes (BMs) are specialized forms of ex­ tracellular matrix composed of collagens, noncollagenous glycoproteins such as laminin and entactin, and specific pro­ teoglycans. BMs delimit the various anatomic compartments of the lung, anchor epithelial and endothelial cells to the in­ terstitial matrix, and regulate the permeability properties of the alveolar wall. They are believed to provide a substratum for lung epithelial cell growth and differentiation and to play crucial roles in pulmonary morphogenesis. Integrity of the epithelial BM could also playa key role in determining the pattern of structural remodeling following lung injury. For example, disruption of the BM can allow interstitial connec­ tive tissue cells to migrate into areas of airspace exudate with resultant intra-alveolar fibrosis or bronchiolitis obliterans. Type IV collagen is an integral structural component of epithelial and endothelial BMs. It is synthesized by lung epi­ thelial, endothelial, smooth muscle, and perineural cells and by activated lung fibroblasts. The majority of type IV colla­ gen in most tissues is composed of heterotrimers of geneti­ cally distinct o l and a2 chains, i.e., [a1(IV)ha2. How­ ever, sequences corresponding to two less abundant chain types, a3 and a4(IV), have been identified in glomerular basement membrane (GBM) and other tissues. Although the molecular organization of the minor chains has not been fully elucidated, there is evidence for the formation of homopolymers, as well as heterotrimers with one or more of the major chain types. A fifth chain, a5(IV), is a compo­ nent of the GBM and has been assigned to the locus of X-linked Alport's familial nephritis (1-3). The complete amino acid sequences for the human and mouse o l and a2(IV) chains have been reported (4). Recent studies have also shown that the human a 1 and a2(IV) genes are closely linked on the long arm of chromosome 13, on op­ posite DNA strands with an overlapping promoter (5-7). However, the complete primary structure of the a3 and a4 chains and the chromosomal localization of the correspond­ ing genes have not yet been described.