Fibronectin type II (FnII)-like modules regulate gelatinase A activity.
Gelatinase A, a member of the matrix metalloproteinase family, contains three fibronectin type II (FnII)-like modules that are inserted within its catalytic domain. These FnII modules, defined as exosites, play an essential role in targeting the enzyme to matrix macromolecules, a process which can down-regulate membrane-type metalloproteinase-driven progelatinase A activation. The exosite/substrate-directed gelatinase inhibitors has been proposed as an alternative approach to disappointing active site-directed inhibitors, to control gelatinase A activity. In preliminary experiments, we evidenced that long-chain unsaturated fatty acids could bind preferentially to the first FnII module of gelatinase A. This interaction inhibits the activity of this enzyme towards proteins (type I gelatin and collagen) and an octapeptide substrate, with K(i) in the micromolar range. Since gelatinase A-catalyzed matrix proteolysis might display a positive or negative influence (depending on the substrate cleaved), the design of exosite-specific compounds for noncatalytic targeting of gelatinase A would necessitate an extensive degradomic analysis.
Hornebeck
W
W
Laboratoire de Biochimie, CNRS UMR 6198, IFR 53 Biomolécules, Université de Reims-Champagne, Reims, France. william.hornebeck@univ-remis.fr
Bellon
G
G
Emonard
H
H
D020816:Amino Acid Motifs; D005353:Fibronectins / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry* / Q000378:metabolism*; D013379:Substrate Specificity; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
D005353:Fibronectins; D019716:Tissue Inhibitor of Metalloproteinase-2; D020778:Matrix Metalloproteinase 2