Abstract
The immunoregulatory plasma protein alpha 1-microglobulin (alpha 1-m) and the proteinase inhibitor alpha 1-inhibitor-3 (alpha 1I3) form a complex in rat plasma. In the present work, it was demonstrated that the alpha 1I3.alpha 1-m complex has no inhibitory activity, the bait region was not cleaved by low amounts of proteinases, and it was unable to covalently incorporate proteinases. The results also indicated that the thiolester bond of the alpha 1I3.alpha 1-m complex was broken. The alpha 1I3.alpha 1-m complex was cleared from the circulation much faster than native alpha 1I3, with a half-life of approximately 7 min. Structurally, however, the alpha 1I3.alpha 1-m complex was similar to native alpha 1I3 rather than alpha 1I3 cleaved by proteinases. It is speculated that the role of alpha 1-m is to destroy the function of alpha 1I3 by blocking the bait region and breaking the thiolester and causing its physical elimination by rapid clearing from the blood circulation. It is also possible that the formation of complexes between alpha 1-m and alpha 1I3 may serve as a mean to regulate the function of alpha 1-m since its complex with alpha 1I3 is taken up rapidly by cellular receptors for alpha-macroglobulins.
Highlights
The conformational shift of a ll 3 leads to exposure of a domain with high affinity for receptors on hepatocytes and macrophages, resulting in a rapid clearance of the aIls-proteinase complex, a property shared by many a-macroglobulins (Debanne et at., 1976; Van Leuven et at., 1979; Gliemann and Sottrup-Jensen, 1987)
The aI13'al-m complex was purified from rat plasma, and its proteinase inhibitory activities and some structural properties were compared with those of free a113, the rat a2-macroglobulin homologue, The results demonstrate that the proteinase inhibitory activity of aI13'al-m is lost and its thior_--========_....,fTli g
There was no conformational shift of the a lI3'al-m molecule (Fig. 5), which has previously been demonstrated to be the result of proteinase treatment of all3 (Enghild et al, 1989a)
Summary
Vol 270, No., Issue of March 3, pp. 4478-4483, 1995 Printed in U.S.A. lrt-Microglobulin Destroys the Proteinase Inhibitory Activity of lrt-Inhibitor-3 by Complex Formation*. 4478-4483, 1995 Printed in U.S.A. lrt-Microglobulin Destroys the Proteinase Inhibitory Activity of lrt-Inhibitor-3 by Complex Formation*. The immunoregulatory plasma protein al"microglobulin (alom) and the proteinase inhibitor al-inhibitor-3 (aIls) form a complex in rat plasma. It was demonstrated that the alIs'al-m complex has no inhibitory activity, the bait region was not cleaved by low amounts of proteinases, and it was unable to covalently incorporate proteinases. The conformational shift of a ll 3 leads to exposure of a domain with high affinity for receptors on hepatocytes and macrophages, resulting in a rapid clearance of the aIls-proteinase complex, a property shared by many a-macroglobulins (Debanne et at., 1976; Van Leuven et at., 1979; Gliemann and Sottrup-Jensen, 1987). The complex formation between al-m and a ll raised the question whether "l-m could influence the proteinase inhibitory activity or receptor recognition of "113- In this work, the complex was isolated and compared with the native proteinase inhibitor, all3'
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