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doi: 10.1242/10.1242/jcs.00106

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New functional roles for non-collagenous domains of basement membrane collagens

Department of Anatomy, University of California, San Francisco, CA 94143-0452, USA

View larger version (20K): [in a new window]   Fig. 1. (A) Linear structure of human collagen IV chains. Six different genes encode collagen IV chains; each polypeptide is composed of three distinct domains: a cysteine-rich N-terminal 7S domain, a central triple-helical domain with multiple small interruptions (green boxes) and a globular C-terminal non-collagenous NC1 domain. The NC1 and central triple-helical domains are of an equivalent size, whereas the 7S domains are shorter in the case of 3, 4, 5 and 6 compared with 1 and 2. On the basis of sequence homology these different chains can be divided in two groups, the 1-like (1, 3, 5) and the 2-like (2, 4, 6). Assembly of collagen IV chains. (B) The assembly of trimers is dependent first on the association of the NC1 domains, then the triple-helical structure forms and 7S domains are covalently associated. Four trimers interact through their 7S domains in a spider-shaped structure, and two trimers interact head to head through their NC1 domains, forming a sheet structure. Several trimers can also lace together along their triple-helical domain, thickening the structure (Timpl et al., 1981).

View larger version (20K): [in a new window]   Fig. 2. (A) Linear structure of human collagen XV and XVIII 1 chains. The 1 chains of collagen XV and XVIII are structurally homologous; they define a new collagen subfamily, the multiplexin family, on the basis of their central triple-helical domain with multiple long interruptions (green boxes). They are also characterized by a long non-collagenous N-terminal-domain-containing Thrombospondin sequence motif with two splicing variants in human collagen XVIII and a long non-collagenous globular C-terminal domain or NC1 domain. (B) Functional sub-domains of human NC1(XVIII) and protease cleavage sites. The NC1 domain contains three functionally different subdomains: these domains consist of a N-terminal non-covalent trimerization domain necessary for the association of trimers, a hinge domain containing multiple sites sensitive to different proteases and an endostatin globular domain covering a fragment of 20 kDa with anti-angiogenic and anti-branching morphogenesis activities. Numerous enzymes can generate fragments containing endostatin. Cathepsin L and elastase are the most efficient, but in contrast to MMP cleavage leading to accumulation of endostatin, cathepsin L and B degrade the molecule [cleavage sites are indicated according to the data published by Ferreras (Ferreras et al., 2000)].

View larger version (39K): [in a new window]   Fig. 3. Biological activities of immobilized versus soluble NC1 and endostatin fragments. Immobilized NC1 domains from collagen IV, XV and XVIII induce proliferation, survival and migration of different cell types. These effects correlate with an increase in P13K, FAK and paxillin phosphorylation. By contrast, soluble NC1 or endostatin fragments bind to various receptors on the surface of the cells and decrease phosphorylation of PI3K, FAK and paxillin. Endostatin as well as NC1(IV) induces a decrease in the transcription of different genes. Endostatin interacts with VEGF-R2 and thus decreases the binding of VEGF to its receptor; endostatin also interacts directly with MMP-2, inhibiting the activation of the enzyme. Taken together, these soluble fragments act in the opposite way to their original molecules, negatively regulating the proliferation and the migration of different cell types and inducing apoptosis and extracellular matrix disorganization.

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