Molecular modeling of the prekallikrein structure provides insights into high-molecular-weight kininogen binding and zymogen activation.
J Thromb Haemost
; 5(12): 2461-6, 2007 Dec.
Article
de En
| MEDLINE
| ID: mdl-17922805
ABSTRACT
BACKGROUND:
Prekallikrein (PK) plays a central role in the contact system that activates blood coagulation and is involved in the regulation of blood pressure.OBJECTIVES:
To provide three-dimensional structural data for PK and rationalize the molecular basis of substrate recognition and zymogen activation. PATIENTS/METHODS:
The PK homology model was constructed using the coagulation factor (F) XI crystal structure as a template with the program SWISS-MODEL.RESULTS:
The domain organization of the PK apple domains and serine protease is conserved compared to FXI. Surface charge calculations on the PK model revealed that ligand binding to high-molecular-weight kininogen (HK) is predicted to have two key determinants a pocket within the apple 2 domain and a basic channel formed at the interface of apple domains 1 and 4. A hereditary mutation resulting in PK deficiency (Gly104Arg) and the Lys140 alpha-kallikrein cleavage site both disrupt HK binding and are shown to map to opposite sides of the apple 2 domain pocket. The model also describes the differences in the apple 4 domain that prevents dimer formation in PK vs. FXI. A C-terminal extension in the PK serine protease domain is described as a potential substrate for prolylcarboxypeptidase.CONCLUSIONS:
The interaction between PK and HK is mediated by two discrete surfaces formed by the PK A1, A2 and A4 domains with charge likely to be a critical component of the binding. A novel mode of PK activation is postulated to involve prolylcarboxypeptidase cleaving at the C-terminus rather than the activation loop.
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Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Prékallicréine
/
Modèles moléculaires
/
Kininogène de haut poids moléculaire
Type d'étude:
Prognostic_studies
Limites:
Humans
Langue:
En
Journal:
J Thromb Haemost
Sujet du journal:
HEMATOLOGIA
Année:
2007
Type de document:
Article
Pays d'affiliation:
Royaume-Uni