Trapping metalloproteinases in a serpin’s coils

Serpins are a family of proteinase inhibitors that bind to the catalytic sites of serine dependent proteinases. Tissue factor pathway inhibitor (TFPI-) 1, a well studied member of this family, is best known for its ability to limit the clotting cascade. Based on its structural similarity to TFPI-1, the related protein TFPI-2 was expected to play a similar role, and indeed, TFPI-2 can bind various serine proteinases. Nevertheless, TFPI-2 has proved to be a poor inhibitor of these enzymes, so its physiological role has been uncertain. Herman et al. show here that TFPI-2 acts instead on a distinct class of targets, the matrix metalloproteinases, which are required to degrade collagen and other ECM components that are typically not the targets of serine proteinases. This biochemical activity is independent of TFPI-2’s action as a serpin, since it can block MMP activity even when it is pre-incubated with serine proteinases. TFPI-2 is secreted by vascular smooth muscle cells and is abundant in healthy arteries, where it would be expected to protect the vessel intima from degradation by MMPs. The authors focus on atheromatous plaque, a collagen-rich structure that can rupture to cause strokes. Within this plaque, TFPI-2 is enriched in the fibrous cap but is more sparse in the adjoining “shoulder” region, where collagenase-secreting macrophages reside. Because this region of the atheroma is known to be a frequent point of rupture, the authors speculate that it is destabilized by a local imbalance between TFPI-2 and MMPs.