Alpha1-antitrypsin inhibits the activity of the matriptase catalytic domain in vitro.
Matriptase is a type II transmembrane protease that is characterized by an N-terminal transmembrane and multiple extracellular domains, in addition to the conserved extracellular serine protease catalytic domain. The expression pattern of matriptase suggests that this protease may play broad roles in the biology of surface lining epithelial cells. In this study we report that alpha1-antitrypsin (AAT), an endogenous inhibitor of serine proteases, inhibits the catalytic domain of human recombinant matriptase in vitro. Co-incubation of AAT with matriptase (at a molar ratio 1:2) resulted in the formation of heat stable complexes, clearly seen in sodium dodecyl sulfate electrophoresis and Western blots. AAT was found to be a slow, tight-binding inhibitor of the catalytic domain of matriptase with a second order reaction rate constant of 0.31 x 10(3) M(-1)s(-1). Notably, the oxidized form of AAT, which lacks serine protease inhibitor activity, failed to generate matriptase complexes and to inhibit matriptase activity. Since matriptase is involved in a number of physiologic processes, including activation of epithelial sodium channels, our findings offer considerable new insights into new regulatory function of AAT in vivo.
Janciauskiene
Sabina
S
Lund University, Department of Clinical Sciences, The Wallenberg Laboratory, Malmö University Hospital, Malmö, Sweden. sabina.janciauskiene@med.lu.se
Nita
Izabela
I
Subramaniyam
Devipriya
D
Li
Qian
Q
Lancaster
Jack R
JR
Matalon
Sadis
S
D000595:Amino Acid Sequence; D015153:Blotting, Western; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007700:Kinetics; D019272:Leukocyte Elastase / Q000378:metabolism; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D016415:Sequence Alignment; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism*; D000515:alpha 1-Antitrypsin / Q000737:chemistry / Q000378:metabolism*
D000515:alpha 1-Antitrypsin; D012697:Serine Endopeptidases; C485595:matriptase; D019272:Leukocyte Elastase