Mammalian tolloid proteinases: role in growth factor signalling

Abstract

Tolloid proteinases are essential for tissue patterning and extracellular matrix assembly. The members of the family differ in their substrate specificity and activity, despite sharing similar domain organization. The mechanisms underlying substrate specificity and activity are complex, with variation between family members, and depend on both multimerization and substrate interaction. In addition, enhancers, such as Twisted gastrulation (Tsg), promote cleavage of tolloid substrate, chordin, to regulate growth factor signalling. Although Tsg and mammalian tolloid (mTLD) are involved in chordin cleavage, no interaction has been detected between them, suggesting Tsg induces a change in chordin to increase susceptibility to cleavage. All members of the tolloid family bind the N terminus of latent TGFβ‐binding protein‐1, providing support for their role in TGFβ signalling.

Proteolysis of the low density lipoprotein receptor by bone morphogenetic protein-1 regulates cellular cholesterol uptake

“…The structure of BMP1 is highly conserved across species and the protease is required for the maturation of fibrillar collagen from procollagen by proteolytic removal of the C-terminal propeptides 21 . BMP1 is also involved in the formation of the extracellular matrix through the activation of numerous structural proteins and enzymes 21 , and in the generation of growth factors involved in morphogenesis, including the cleavage and activation of members of the TGF-β family 22 . We established that the catalytic activity of BMP1 is required for LDLR cleavage through use of an active site directed inhibitor and through mutation of a critical residue in the active site of the protease.…”

BMP1.3 protein as potential target in treatment of fibrosis

“…The cDNA sequence of BMP1 showed high degree of similarity also to the Drosophila Tolloid metalloproteinase (4). In human and mice, the gene encoding BMP1 produces alternatively spliced transcripts with preserved domain structure, where the long isoform has an organization of domains identical to the Drosophila Tolloid and is designated mammalian Tolloid (mTLD) BMP1/TLD-like proteases are involved in processing a wide range of extracellular matrix (ECM) precursors required for normal tissue assembly (13). Examples of such ECM precursor proteins are procollagens I-III, minor fibrillar procollagens, small leucine-rich proteoglycans (such as decorin, osteoglycin, biglycan), basement membrane components (laminin 332, collagen VII) and mineralization factors (dentin sialophosphoprotein, dentin matrix protein) (14).…”

“…Further, BMP1/TLD-like proteases are engaged in release of TGFβ superfamily members from their inhibitory complexes (e.g. TGFβ1, BMP2, -4 and -7), which in turn regulates developmental patterning and tissue homeostasis (13). In mice, Bmp1 gene appears to be required for normal embryo development, and homozygous mutants with complete deletion of Bmp1 are lethal because of herniation of the gut combined with failure of ventral body wall closure (15,16).…”

Fragments generated upon extracellular matrix remodeling: Biological regulators and potential drugs

“…ADAMTSs and tolloid proteases [187,188] (Figure 1). Cysteine and aspartate proteinases (cathepsins E, L, B, and S) and serine proteases (plasmin, thrombin, elastase, furin and cathepsin G) also participate in the release of matricryptins/matrikines (Figure 1).…”