Initial activation of proMMP1 Authored: Jupe, S, 2011-09-09 EC Number: 3.4.21 Edited: Jupe, S, 2012-02-21 ProMMP1 has several activators including plasmin (Eeckhout & Vaes 1977, Werb et al. 1977, Santala et al. 1999), trypsin (Grant et al. 1987, Saunders et al. 2005), plasma kallikrein (Nagase et al. 1982, Saunders et al. 2005), chymase (Saarinen et al. 1994, Suzuki et al. 1995, Saunders et al. 2005), tryptase (Gruber et al. 1989, Suzuki et al. 1995, Saunders et al. 2005), neutrophil elastase, cathepsin G (Saunders et al. 2005) and trypsin-2 (Moilanen et al. 2003). Concanavalin A (ConA) was the first cellular treatment that yielded active MMPs in culture, inducing the cellular activation of MMP1 likely through MMP14 activity (Overall and Sodek 1990).Trypsin-like serine proteinases are believed to remove 34-36 residues from the N-terminus of the secreted pro-enzyme, equivalent to positions 53-55 of the UniProt cannonical sequence which includes a signal peptide. Removal of this region is sufficient to destabilize the Cys92-Zn2+ stabilizing bond (numbered according to the Uniprot canonical sequence, Cys73 when numbered from the N terminus of the secreted peptide as typically represented in the literature) and partially activate enzyme activity. This intermediate form then undergoes autocatalysis at Thr83-Leu84 producing an MMP1 with about 20% of full collagenase activity (Suzuki et al. 1990). Full activation is brought about by a further cleavage at Gln99-Phe100. When first reported, considerable debate surrounded the activation of this archetypical MMP. Divergence of opinion resulted when competing groups studied activation in vitro using chemicals (organomercurials such as aminophenylmecuricacetate), which yield a different autolytic cleavage site in the protease susceptible loop when compared with the site cut by serine proteases such as trypsin. Different specific activities result, but in general the final autolytic cleavage site for all MMPs is the homologous Phe or Tyr at position 100 or 101. When the active enzyme commences here, full activity is realised due to the salt bridge forming between the N-terminal primary amine of the conserved Phe or Tyr with an Asp on helix C that in turn salt bridges to the active site Glu. Termini either side of this position do not result in full activity. Pubmed10567688 Pubmed12731883 Pubmed15870107 Pubmed197917 Pubmed2174435 Pubmed2176865 Pubmed2553780 Pubmed3032947 Pubmed6279161 Pubmed66627 Pubmed7826345 Pubmed8027075 Reactome Database ID Release 431592316 Reactome, http://www.reactome.org ReactomeREACT_118608 Reviewed: Butler, GS, 2012-02-28 Reviewed: Overall, CM, 2012-02-28