Detection of truncated isoforms of human neuroserpin lacking the reactive center loop: Implications in noninhibitory role

IUBMB Life ◽  
2021 ◽  
Author(s):  
Sana Fatima ◽  
Shoyab Ansari ◽  
Shadabi Bano ◽  
Shahzaib Ahamad ◽  
Hassan Mubarak Ishqi ◽  
...  
Keyword(s):  
Reactive Center Loop ◽  
Reactive Center ◽  
Truncated Isoforms

scholarly journals Serpin reactive center loop mobility is required for inhibitor function but not for enzyme recognition.

1994 ◽  
Vol 269 (44) ◽  
pp. 27657-27662 ◽  
Author(s):  
D A Lawrence ◽  
S T Olson ◽  
S Palaniappan ◽  
D Ginsburg
Keyword(s):  
Reactive Center Loop ◽  
Reactive Center ◽  
Enzyme Recognition

A reactive center loop–based prediction platform to enhance the design of therapeutic SERPINs

2021 ◽  
Vol 118 (45) ◽  
pp. e2108458118
Author(s):  
Wariya Sanrattana ◽  
Thibaud Sefiane ◽  
Simone Smits ◽  
Nadine D. van Kleef ◽  
Marcel H. Fens ◽  
...  
Keyword(s):  
Cleavage Site ◽  
Serine Proteases ◽  
Protein C ◽  
Activated Protein C ◽  
Reactive Center Loop ◽  
Physiological Processes ◽  
Naturally Occurring ◽  
Reactive Center ◽  
Insight Into

Serine proteases are essential for many physiological processes and require tight regulation by serine protease inhibitors (SERPINs). A disturbed SERPIN–protease balance may result in disease. The reactive center loop (RCL) contains an enzymatic cleavage site between the P1 through P1’ residues that controls SERPIN specificity. This RCL can be modified to improve SERPIN function; however, a lack of insight into sequence–function relationships limits SERPIN development. This is complicated by more than 25 billion mutants needed to screen the entire P4 to P4’ region. Here, we developed a platform to predict the effects of RCL mutagenesis by using α1-antitrypsin as a model SERPIN. We generated variants for each of the residues in P4 to P4’ region, mutating them into each of the 20 naturally occurring amino acids. Subsequently, we profiled the reactivity of the resulting 160 variants against seven proteases involved in coagulation. These profiles formed the basis of an in silico prediction platform for SERPIN inhibitory behavior with combined P4 to P4’ RCL mutations, which were validated experimentally. This prediction platform accurately predicted SERPIN behavior against five out of the seven screened proteases, one of which was activated protein C (APC). Using these findings, a next-generation APC-inhibiting α1-antitrypsin variant was designed (KMPR/RIRA; / indicates the cleavage site). This variant attenuates blood loss in an in vivo hemophilia A model at a lower dosage than the previously developed variant AIKR/KIPP because of improved potency and specificity. We propose that this SERPIN-based RCL mutagenesis approach improves our understanding of SERPIN behavior and will facilitate the design of therapeutic SERPINs.

scholarly journals Crystal Structure of Monomeric Native Antithrombin Reveals a Novel Reactive Center Loop Conformation

2006 ◽  
Vol 281 (46) ◽  
pp. 35478-35486 ◽  
Author(s):  
Daniel J. D. Johnson ◽  
Jonathan Langdown ◽  
Wei Li ◽  
Stephan A. Luis ◽  
Trevor P. Baglin ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Reactive Center Loop ◽  
Reactive Center ◽  
Loop Conformation

scholarly journals Pyrexia and acidosis act independently of neutrophil elastase reactive center loop cleavage to effect cortisol release from corticosteroid‐binding globulin

2020 ◽  
Vol 29 (12) ◽  
pp. 2495-2509
Author(s):  
Emily J. Meyer ◽  
David J. Torpy ◽  
Anastasia Chernykh ◽  
Morten Thaysen‐Andersen ◽  
Marni A. Nenke ◽  
...  
Keyword(s):  
Neutrophil Elastase ◽  
Reactive Center Loop ◽  
Reactive Center ◽  
Corticosteroid Binding Globulin ◽  
Cortisol Release

The Reactive-center Loop of Active PAI-1 is Folded Close to the Protein Core and can be Partially Inserted

2004 ◽  
Vol 335 (3) ◽  
pp. 823-832 ◽  
Author(s):  
Peter Hägglöf ◽  
Fredrik Bergström ◽  
Malgorzata Wilczynska ◽  
Lennart B.-Å Johansson ◽  
Tor Ny
Keyword(s):  
Protein Core ◽  
Reactive Center Loop ◽  
Reactive Center ◽  
Pai 1

scholarly journals Distinct encounter complexes of PAI-1 with plasminogen activators and vitronectin revealed by changes in the conformation and dynamics of the reactive center loop

2015 ◽  
Vol 25 (2) ◽  
pp. 499-510 ◽  
Author(s):  
Tihami Qureshi ◽  
Sumit Goswami ◽  
Carlee S. McClintock ◽  
Matthew T. Ramsey ◽  
Cynthia B. Peterson
Keyword(s):  
Plasminogen Activators ◽  
Reactive Center Loop ◽  
Reactive Center ◽  
Pai 1
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