Metals affect the structure and activity of human plasminogen activator inhibitor‐1. I. Modulation of stability and protease inhibition
Human plasminogen activator inhibitor type 1 (PAI‐1) is a serine protease inhibitor with a metastable active conformation. Under physiological conditions, half of the inhibitor transitions to a latent state within 1–2 h. The interaction between PAI‐1 and the plasma protein vitronectin prolongs this...
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Published in | Protein science Vol. 20; no. 2; pp. 353 - 365 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
Hoboken
Wiley Subscription Services, Inc., A Wiley Company
01.02.2011
Wiley Subscription Services, Inc |
Subjects | |
Online Access | Get full text |
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Summary: | Human plasminogen activator inhibitor type 1 (PAI‐1) is a serine protease inhibitor with a metastable active conformation. Under physiological conditions, half of the inhibitor transitions to a latent state within 1–2 h. The interaction between PAI‐1 and the plasma protein vitronectin prolongs this active lifespan by ∼50%. Previously, our group demonstrated that PAI‐1 binds to resins using immobilized metal affinity chromatography (Day, U.S. Pat. 7,015,021 B2, March 21, 2006). In this study, the effect of these metals on function and stability was investigated by measuring the rate of the transition from the active to latent conformation. All metals tested showed effects on stability, with the majority falling into one of two types depending on their effects. The first type of metal, which includes magnesium, calcium and manganese, invoked a slight stabilization of the active conformation of PAI‐1. A second category of metals, including cobalt, nickel and copper, showed the opposite effects and a unique vitronectin‐dependent modulation of PAI‐1 stability. This second group of metals significantly destabilized PAI‐1, although the addition of vitronectin in conjunction with these metals resulted in a marked stabilization and slower conversion to the latent conformation. In the presence of copper and vitronectin, the half‐life of active PAI‐1 was extended to 3 h, compared to a half‐life of only ∼30 min with copper alone. Nickel had the largest effect, reducing the half‐life to ∼5 min. Together, these data demonstrate a heretofore‐unknown role for metals in modulating PAI‐1 stability. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 C.B.P was supported by Grant-in-Aid 10GRNT4430033 from the American Heart Association and I. M. V. was supported by NIH grant R01-HL-080018. |
ISSN: | 0961-8368 1469-896X |
DOI: | 10.1002/pro.568 |