Abstract
The defence collagens C1q and mannose-binding lectin (MBL) are immune recognition proteins that associate with the serine proteinases C1r/C1s and MBL-associated serine proteases (MASPs) to trigger activation of complement, a major innate immune system. Bone morphogenetic protein-1 (BMP-1)/tolloid-like proteinases (BTPs) are metalloproteinases with major roles in extracellular matrix assembly and growth factor signalling. Despite their different functions, C1r/C1s/MASPs and BTPs share structural similarities, including a specific CUB-EGF-CUB domain arrangement found only in these enzymes that mediates interactions with collagen-like proteins, suggesting a possible functional relationship. Here we investigated the potential interactions between the defence collagens C1q and MBL and the BTPs BMP-1 and mammalian tolloid-like-1 (mTLL-1). C1q and MBL bound to immobilized BMP-1 and mTLL-1 with nanomolar affinities. These interactions involved the collagen-like regions of the defence collagens and were inhibited by pre-incubation of C1q or MBL with their cognate complement proteinases. Soluble BMP-1 and mTLL-1 did not inhibit complement activation and the defence collagens were neither substrates nor inhibitors of BMP-1. Finally, C1q co-localized with BMP-1 in skin biopsies following melanoma excision and from patients with recessive dystrophic epidermolysis bullosa. The observed interactions provide support for a functional link between complement and BTPs during inflammation and tissue repair.
Highlights
The complement system is a complex extracellular protein cascade that, when triggered by interactions with self or non-self molecules, results in the production of inflammatory mediators and a membrane attack complex that helps destroy invading cells
The defence collagens C1q and mannose-binding lectin (MBL) interact with Bone morphogenetic protein-1 (BMP-1) and mammalian Tolloid-like-1 (mTLL-1)
BMP-1 and mTLL-1 were immobilized on the surface of a sensor chip and the defence collagens injected over the immobilized proteinases in the presence of Ca2+ ions
Summary
The complement system is a complex extracellular protein cascade that, when triggered by interactions with self or non-self molecules, results in the production of inflammatory mediators and a membrane attack complex that helps destroy invading cells (for recent reviews see[1,2]). Bone morphogenetic protein-1 (BMP-1)/tolloid-like proteinases, otherwise known as BTPs, are extracellular zinc-dependent metalloproteinases whose main roles are in extracellular matrix assembly and growth factor signalling[7] They control collagen assembly by cleavage of propeptides from precursor forms of collagens, lysyl oxidases and small leucine rich proteoglycans, and they activate growth factors by maturation of latent forms or cleavage of growth factor antagonists. BTP family members in humans include bone morphogenetic protein-1 (BMP-1), mammalian Tolloid (mTLD), and mammalian Tolloid-like-1 (mTLL-1) and -2 (mTLL-2).They have been shown to control many aspects of development, growth and tissue repair, and are involved in diseases such as cancer and fibrosis[7] Despite their different roles, proteins of the complement and BTP systems share many similarities. We describe interactions between C1q and MBL and the BTPs BMP-1 and mTLL-1 that provide further support for such a functional connection
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