Rational Design of Protein C Activators
In addition to its procoagulant and proinflammatory functions mediated by cleavage of fibrinogen and PAR1, the trypsin-like protease thrombin activates the anticoagulant protein C in a reaction that requires the cofactor thrombomodulin and the endothelial protein C receptor. Once in the circulation, activated protein C functions as an anticoagulant, anti-inflammatory and regenerative factor. Hence, availability of a protein C activator would afford a therapeutic for patients suffering from thrombotic disorders and a diagnostic tool for monitoring the level of protein C in plasma. Here, we present a fusion protein where thrombin and the EGF456 domain of thrombomodulin are connected through a peptide linker. The fusion protein recapitulates the functional and structural properties of the thrombin-thrombomodulin complex, prolongs the clotting time by generating pharmacological quantities of activated protein C and effectively diagnoses protein C deficiency in human plasma. Notably, these functions do not require exogenous thrombomodulin, unlike other anticoagulant thrombin derivatives engineered to date. These features make the fusion protein an innovative step toward the development of protein C activators of clinical and diagnostic relevance.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2017 |
|---|---|
| Erschienen: |
2017 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:7 |
|---|---|
| Enthalten in: |
Scientific reports - 7(2017) vom: 15. März, Seite 44596 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Barranco-Medina, Sergio [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Endothelial Protein C Receptor |
|---|
| Anmerkungen: |
Date Completed 06.11.2018 Date Revised 29.01.2022 published: Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1038/srep44596 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM269847227 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM269847227 | ||
| 003 | DE-627 | ||
| 005 | 20231226193717.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231224s2017 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/srep44596 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0899.xml |
| 035 | |a (DE-627)NLM269847227 | ||
| 035 | |a (NLM)28294177 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Barranco-Medina, Sergio |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Rational Design of Protein C Activators |
| 264 | 1 | |c 2017 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 06.11.2018 | ||
| 500 | |a Date Revised 29.01.2022 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a In addition to its procoagulant and proinflammatory functions mediated by cleavage of fibrinogen and PAR1, the trypsin-like protease thrombin activates the anticoagulant protein C in a reaction that requires the cofactor thrombomodulin and the endothelial protein C receptor. Once in the circulation, activated protein C functions as an anticoagulant, anti-inflammatory and regenerative factor. Hence, availability of a protein C activator would afford a therapeutic for patients suffering from thrombotic disorders and a diagnostic tool for monitoring the level of protein C in plasma. Here, we present a fusion protein where thrombin and the EGF456 domain of thrombomodulin are connected through a peptide linker. The fusion protein recapitulates the functional and structural properties of the thrombin-thrombomodulin complex, prolongs the clotting time by generating pharmacological quantities of activated protein C and effectively diagnoses protein C deficiency in human plasma. Notably, these functions do not require exogenous thrombomodulin, unlike other anticoagulant thrombin derivatives engineered to date. These features make the fusion protein an innovative step toward the development of protein C activators of clinical and diagnostic relevance | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Endothelial Protein C Receptor |2 NLM | |
| 650 | 7 | |a Peptides |2 NLM | |
| 650 | 7 | |a Protein C |2 NLM | |
| 650 | 7 | |a Recombinant Fusion Proteins |2 NLM | |
| 650 | 7 | |a Thrombomodulin |2 NLM | |
| 700 | 1 | |a Murphy, Mary |e verfasserin |4 aut | |
| 700 | 1 | |a Pelc, Leslie |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Zhiwei |e verfasserin |4 aut | |
| 700 | 1 | |a Di Cera, Enrico |e verfasserin |4 aut | |
| 700 | 1 | |a Pozzi, Nicola |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Scientific reports |d 2011 |g 7(2017) vom: 15. März, Seite 44596 |w (DE-627)NLM215703936 |x 2045-2322 |7 nnns |
| 773 | 1 | 8 | |g volume:7 |g year:2017 |g day:15 |g month:03 |g pages:44596 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/srep44596 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 7 |j 2017 |b 15 |c 03 |h 44596 | ||