Advanced

Screening the molecular surface of human anticoagulant protein C: a search for interaction sites

Villoutreix, Bruno O.; Covell, David G.; Blom, Anna LU ; Wallqvist, Anders; Friedrich, Ute and Dahlbäck, Björn LU (2001) In Journal of Computer-Aided Molecular Design 15(1). p.13-27
Abstract
Protein C (PC), a 62 kDa multi-modular zymogen, is activated to an anticoagulant serine protease (activated PC or APC) by thrombin bound to thrombomodulin on the surface of endothelial cells. PC/APC interacts with many proteins and the characterisation of these interactions is not trivial. However, molecular modelling methods help to study these complex biological processes and provide basis for rational experimental design and interpretation of the results. PC/APC consists of a Gla domain followed by two EGF modules and a serine protease domain. In this report, we present two structural models for full-length APC and two equivalent models for full-length PC, based on the X-ray structures of Gla-domainless APC and of known serine protease... (More)
Protein C (PC), a 62 kDa multi-modular zymogen, is activated to an anticoagulant serine protease (activated PC or APC) by thrombin bound to thrombomodulin on the surface of endothelial cells. PC/APC interacts with many proteins and the characterisation of these interactions is not trivial. However, molecular modelling methods help to study these complex biological processes and provide basis for rational experimental design and interpretation of the results. PC/APC consists of a Gla domain followed by two EGF modules and a serine protease domain. In this report, we present two structural models for full-length APC and two equivalent models for full-length PC, based on the X-ray structures of Gla-domainless APC and of known serine protease zymogens. The overall elongated shape of the models is further cross-validated using size exclusion chromatography which allows evaluation of the Stokes radius (rs for PC = 33.15 A; rs for APC = 34.19 A), frictional ratio and axial ratio. We then propose potential binding sites at the surface of PC/APC using surface hydrophobicity as a determinant of the preferred sites of intermolecular recognition. Most of the predicted binding sites are consistent with previously reported experimental data, while some clusters highlight new regions that should be involved in protein-protein interactions. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
coagulation, protein C, protein interaction, protein modelling, thrombin
in
Journal of Computer-Aided Molecular Design
volume
15
issue
1
pages
13 - 27
publisher
Kluwer
external identifiers
  • pmid:11219426
  • scopus:0035144327
ISSN
1573-4951
DOI
10.1023/A:1011158717139
language
English
LU publication?
yes
id
cc46aab3-9097-4281-9882-554963bfe958 (old id 1120506)
date added to LUP
2008-07-17 09:56:26
date last changed
2018-10-03 11:38:35
@article{cc46aab3-9097-4281-9882-554963bfe958,
  abstract     = {Protein C (PC), a 62 kDa multi-modular zymogen, is activated to an anticoagulant serine protease (activated PC or APC) by thrombin bound to thrombomodulin on the surface of endothelial cells. PC/APC interacts with many proteins and the characterisation of these interactions is not trivial. However, molecular modelling methods help to study these complex biological processes and provide basis for rational experimental design and interpretation of the results. PC/APC consists of a Gla domain followed by two EGF modules and a serine protease domain. In this report, we present two structural models for full-length APC and two equivalent models for full-length PC, based on the X-ray structures of Gla-domainless APC and of known serine protease zymogens. The overall elongated shape of the models is further cross-validated using size exclusion chromatography which allows evaluation of the Stokes radius (rs for PC = 33.15 A; rs for APC = 34.19 A), frictional ratio and axial ratio. We then propose potential binding sites at the surface of PC/APC using surface hydrophobicity as a determinant of the preferred sites of intermolecular recognition. Most of the predicted binding sites are consistent with previously reported experimental data, while some clusters highlight new regions that should be involved in protein-protein interactions.},
  author       = {Villoutreix, Bruno O. and Covell, David G. and Blom, Anna and Wallqvist, Anders and Friedrich, Ute and Dahlbäck, Björn},
  issn         = {1573-4951},
  keyword      = {coagulation,protein C,protein interaction,protein modelling,thrombin},
  language     = {eng},
  number       = {1},
  pages        = {13--27},
  publisher    = {Kluwer},
  series       = {Journal of Computer-Aided Molecular Design},
  title        = {Screening the molecular surface of human anticoagulant protein C: a search for interaction sites},
  url          = {http://dx.doi.org/10.1023/A:1011158717139},
  volume       = {15},
  year         = {2001},
}