Degradation of cross-linked fibrin by matrix metalloproteinase 3 (stromelysin 1): hydrolysis of the gamma Gly 404-Ala 405 peptide bond.
Matrix metalloproteinases (MMPs) can degrade a number of proteins that constitute the extracellular matrix. Previous studies have shown that atherosclerotic plaques contain substantial amounts of fibrin(ogen)-related antigen, and more recently, MMPs have been identified in such lesions. The hypothesis that MMPs play a role in the degradation of fibrinogen (Fg) and cross-linked fibrin (XL-Fb) was investigated. Fibrinogen became thrombin-unclottable when treated with matrix metalloproteinase 3 (MMP-3, stromelysin 1) but not with matrix metalloproteinase 2 (MMP-2, gelatinase A). Incubation of XL-Fb clots (made with 125I-Fg) with MMP-3 resulted in complete lysis after 24 h. A D monomer-like fragment was generated by MMP-3 degradation of fibrinogen, XL-Fb, and fragment DD. Immunoreactivity with monoclonal antibody (MoAb)/4-2 (anti-gamma 392-406) but not with MoAb/4A5 (anti-gamma 397-411) suggested that a major cleavage site was within the sequence participating in the cross-linking of two gamma-chains. NH2-terminal sequence analysis of they gamma-chain of the D monomer-like fragment and of a dipeptide isolated from the MMP-3 digest of XL-fibrin identified the hydrolysis of the gamma Gly 404-Ala 405 peptide bond. These data indicate that the degradation of Fg and XL-Fb by MMP-3 is specific and different from plasmin. This mechanism of fibrinolysis might be of relevance in wound healing, inflammation, atherosclerosis, and other pathophysiological processes.
Bini
A
A
Laboratory of Blood Coagulation Biochemistry, Lindsley F. Kimball Research Institute, New York Blood Center, New York 10021, USA. abini@server.nybc.org
Itoh
Y
Y
Kudryk
B J
BJ
Nagase
H
H
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology; D001777:Blood Coagulation / Q000502:physiology; D017364:Collagenases / Q000378:metabolism; D003488:Cyanogen Bromide; D005337:Fibrin / Q000378:metabolism*; D005338:Fibrin Fibrinogen Degradation Products / Q000737:chemistry / Q000378:metabolism; D005340:Fibrinogen / Q000737:chemistry / Q000378:metabolism*; D005341:Fibrinolysin / Q000378:metabolism; D018093:Gelatinases / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D020781:Matrix Metalloproteinase 1; D020778:Matrix Metalloproteinase 2; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000378:metabolism; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D017421:Sequence Analysis; D013379:Substrate Specificity
D000911:Antibodies, Monoclonal; D005338:Fibrin Fibrinogen Degradation Products; D010455:Peptides; C036309:fibrin fragment D; D005973:Glutamine; D005337:Fibrin; D005340:Fibrinogen; D005341:Fibrinolysin; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1; D003488:Cyanogen Bromide