1999
DOI: 10.1074/jbc.274.25.17511
|View full text |Cite
|
Sign up to set email alerts
|

Accelerated Conversion of Human Plasminogen Activator Inhibitor-1 to Its Latent Form by Antibody Binding

Abstract: The serpin plasminogen activator inhibitor-1 (PAI-1) slowly converts to an inactive latent form by inserting a major part of its reactive center loop (RCL) into its ␤-sheet A. A murine monoclonal antibody (MA-33B8), raised against the human plasminogen activator (tPA)⅐PAI-1 complex, rapidly inactivates PAI-1. Results presented here indicate that MA-33B8 induces acceleration of the active-to-latent conversion. The antibodyinduced inactivation of PAI-1 labeled with the fluorescent probe N,N-dimethyl-N-(acetyl)-N… Show more

Help me understand this report

Search citation statements

Order By: Relevance

Paper Sections

Select...
2
1
1
1

Citation Types

7
96
0

Year Published

2000
2000
2015
2015

Publication Types

Select...
9

Relationship

0
9

Authors

Journals

citations
Cited by 73 publications
(103 citation statements)
references
References 26 publications
7
96
0
Order By: Relevance
“…To determine if CDE-096 might instead reduce the rate of this transition, studies were performed using a PAI-1 variant, PAI-1 S338C-NBD , previously shown to report the conformational change associated with RCL insertion into sA (44). PAI-1 S338C-NBD is a variant with a NBD probe conjugated to a cysteine substitution at the P9 position of the RCL, and it shows a significant enhancement in NBD fluorescence on conversion to the latent structure.…”
Section: Resultsmentioning
confidence: 99%
“…To determine if CDE-096 might instead reduce the rate of this transition, studies were performed using a PAI-1 variant, PAI-1 S338C-NBD , previously shown to report the conformational change associated with RCL insertion into sA (44). PAI-1 S338C-NBD is a variant with a NBD probe conjugated to a cysteine substitution at the P9 position of the RCL, and it shows a significant enhancement in NBD fluorescence on conversion to the latent structure.…”
Section: Resultsmentioning
confidence: 99%
“…prelatent PAI-1 in Fig. 10) (13). Subsequent mutagenesis studies indicated that the epitope for MA-33B8 includes the loops between ␣-hD and ␤-s2A and between ␤-s2C and ␤-s3C and also includes the residues proceeding ␤-s3A (10,56).…”
Section: Discussionmentioning
confidence: 99%
“…Interestingly, this epitope is adjacent to ␣-hD, which is involved in binding of AZ3976, allowing speculations that the kinetic stability of active PAI-1 is sensitive to its structural integrity in this region. MA-33B8 is a monoclonal antibody against human PAI-1, which also inhibits PAI-1 by accelerating latency transition (13). MA-33B8 did bind both to latent PAI-1 and to the complex between tPA and PAI-1 at a faster rate compared with active PAI-1, and it was suggested that the antibody binding epitope was more exposed in a prelatent conformation of PAI-1 (e.g.…”
Section: Discussionmentioning
confidence: 99%
“…This PAI-1 neutralizing monoclonal antibody, MA-33B8, acted in a dose-responsive manner, but a non-neutralizing antibody MA-19A5 had no such action (Figure 8). It has been suggested that MA-33B8 inactivates PAI-1-stab through acceleration of the conversion of the active conformation to the latent conformation (Vleugels et al, 1998;Verhamme et al, 1999). Thus the reactive site loop in PAI-1 may be responsible for the apoptosis-inhibiting function.…”
Section: The Domain Of Pai-1 Responsible For Inhibition Of Apoptosismentioning
confidence: 99%