Serpin-like properties of alpha1-antitrypsin Portland towards furin convertase.
Recent studies have demonstrated that a serpin variant, alpha1-antitrypsin Portland (AT-PDX), can inhibit the mammalian convertase furin. Here, we examine the mechanism by which this inhibition takes place. We find that furin, which does not belong to the trypsin-like serine protease family, the usual targets of serpins, forms an SDS-heat denaturation-resistant complex with AT-PDX both in vitro and in vivo. AT-PDX inhibited furin with an association rate constant (k(ass)) of 1.5 x 10(6) M(-1) s(-1) which is similar to k(ass) values reported for serpins with trypsin-like enzymes. These results illustrate that AT can be modified to act essentially as a suicide inhibitor of furin, an enzyme of the subtilase superfamily of serine proteases.
Dufour
E K
EK
Department of Pharmacology, Faculty of Medicine, Université de Sherbrooke, Que., Canada.
Denault
J B
JB
Hopkins
P C
PC
Leduc
R
R
D045683:Furin; D006358:Hot Temperature; D006801:Humans; D007700:Kinetics; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding; D011489:Protein Denaturation; D011994:Recombinant Proteins; D013381:Subtilisins / Q000037:antagonists & inhibitors*; D000515:alpha 1-Antitrypsin / Q000235:genetics* / Q000378:metabolism
D010446:Peptide Fragments; D011994:Recombinant Proteins; D000515:alpha 1-Antitrypsin; D013381:Subtilisins; D045683:Furin