Collagen fibrillogenesis: fibronectin, integrins, and minor collagens as organizers and nucleators

Abstract

Collagens are triple helical proteins that occur in the extracellular matrix (ECM) and at the cell-ECM interface. There are more than 30 collagens and collagen-related proteins but the most abundant are collagens I and II that exist as D-periodic (where D = 67 nm) fibrils. The fibrils are of broad biomedical importance and have central roles in embryogenesis, arthritis, tissue repair, fibrosis, tumor invasion, and cardiovascular disease. Collagens I and II spontaneously form fibrils in vitro, which shows that collagen fibrillogenesis is a selfassembly process. However, the situation in vivo is not that simple; collagen I-containing fibrils do not form in the absence of fibronectin, fibronectin-binding and collagen-binding integrins, and collagen V. Likewise, the thin collagen II-containing fibrils in cartilage do not form in the absence of collagen XI. Thus, in vivo, cellular mechanisms are in place to control what is otherwise a protein self-assembly process. This review puts forward a working hypothesis for how fibronectin and integrins (the organizers) determine the site of fibril assembly, and collagens V and XI (the nucleators) initiate collagen fibrillogenesis.

Figure 1

Schematic of the 10 + 4 microfibril structure of a thin cartilage collagen fibril. A pair of collagen XI microfibrils comprise half of a 4 microfibril core surrounded by 10 microfibrils at the surface. The collagen XI/IX/II assembly is a crosslinked heteropolymer, as is V/I, and is an important component of the fibril assembly mechanism. Blue: collagen II molecules; yellow: collagen XI molecules; red: collagen IX molecules. The N-terminal thrombospondin-like domains of collagen XI (yellow) are shown extending from the core microfibrils onto the fibril surface (model kindly provided by Dr David Eyre, University of Washington, Seattle).

Figure 2

Hypothetical model of collagen fibril nucleation at the plasma membrane. (1) Dimeric FN (black) binds to α5β1 integrins (green). (2) Engagement of the integrin with the cytoskeleton (red lines) causes a conformational change in FN with subsequent fibril formation. Additional receptors (orange bars) bind FN. (3) Collagen I, procollagen I (black), and collagen V (purple) engage with FN at the fibril surface to facilitate collagen fibril formation. Decorin (interlocking dimers) shown bound to procollagen. (4) Activated collagen integrins (e.g. α2β1) bind collagen and induce a conformation change that facilitates fibril formation. (5) Collagen fibril formation at the cell surface. (6) Interactions between collagen fibrils (e.g. including tenascin-X and decorin) determine fibril diameter, organization, and spacing. Parts of the schematic are adapted from Mao and Schwarzbauer [8] and Bristow et al. [66].