A theoretical model for the Gla-TSR-EGF-1 region of the anticoagulant cofactor protein S

From biostructural pathology to species-specific cofactor activity

Bruno Villoutreix, Olle Teleman, Björn Dahlbäck

Research output: Contribution to journalArticleScientificpeer-review

34 Citations (Scopus)

Abstract

Protein S (PS), which functions as a species-specific anticoagulant cofactor to activated protein C (APC), is a mosaic protein that interacts with the phospholipid membrane via its γ-carboxyglutamate-rich (Gla) module. This module is followed by the thrombin-sensitive region (TSR), sensitive to thrombin cleavage, four epidermal growth factor (EGF)-like modules and a last region referred to as the sex hormone binding globulin (SHBG) domain. Of these, the TSR and the first EGF-like regions have been shown to be important for the species-specific interaction with APC. Difficulties in crystallising PS have so far hindered its study at the atomic level. Here, we report theoretical models for the Gla and EGF-1 modules of human PS constructed using prothrombin and factor X experimental structures. The TSR was built interactively. Analysis of the model linked with the large body of biochemical literature on PS and related proteins leads to suggestions that (i) the TSR stabilises the calcium-loaded Gla module through hydrophobic and ionic interactions and its conformation depends on the presence of the Gla module; (ii) the TSR does not form a calcium binding site but is protected from thrombin cleavage in the calcium-loaded form owing to short secondary structure elements and close contact with the Gla module; (iii) the PS missense mutations in this region are consistent with the structural data, except in one case which needs further investigation; and (iv) the two PS ‘faces’ involving regions of residues Arg49–Gln52–Lys97 (TSR-EGF-1) and Thr103–Pro106 (EGF-1) may be involved in species-specific interactions with APC as they are richer in nonconservative substitution when comparing human and bovine protein S. This preliminary model helps to plan future experiments and the resulting data will be used to further validate and optimise the present structure.

Original languageEnglish
Pages (from-to)293 - 304
Number of pages12
JournalJournal of Computer-Aided Molecular Design
Volume11
Issue number3
DOIs
Publication statusPublished - 1997
MoE publication typeA1 Journal article-refereed

Fingerprint

anticoagulants
thrombin
Protein S
pathology
Pathology
Epidermal Growth Factor
Thrombin
Anticoagulants
Theoretical Models
proteins
Proteins
modules
Protein C
Calcium
calcium
Factor X
Sex Hormone-Binding Globulin
cleavage
prothrombin
Prothrombin

Cite this

@article{a3d92936de72461dbce20b9aa4ef972d,
title = "A theoretical model for the Gla-TSR-EGF-1 region of the anticoagulant cofactor protein S: From biostructural pathology to species-specific cofactor activity",
abstract = "Protein S (PS), which functions as a species-specific anticoagulant cofactor to activated protein C (APC), is a mosaic protein that interacts with the phospholipid membrane via its γ-carboxyglutamate-rich (Gla) module. This module is followed by the thrombin-sensitive region (TSR), sensitive to thrombin cleavage, four epidermal growth factor (EGF)-like modules and a last region referred to as the sex hormone binding globulin (SHBG) domain. Of these, the TSR and the first EGF-like regions have been shown to be important for the species-specific interaction with APC. Difficulties in crystallising PS have so far hindered its study at the atomic level. Here, we report theoretical models for the Gla and EGF-1 modules of human PS constructed using prothrombin and factor X experimental structures. The TSR was built interactively. Analysis of the model linked with the large body of biochemical literature on PS and related proteins leads to suggestions that (i) the TSR stabilises the calcium-loaded Gla module through hydrophobic and ionic interactions and its conformation depends on the presence of the Gla module; (ii) the TSR does not form a calcium binding site but is protected from thrombin cleavage in the calcium-loaded form owing to short secondary structure elements and close contact with the Gla module; (iii) the PS missense mutations in this region are consistent with the structural data, except in one case which needs further investigation; and (iv) the two PS ‘faces’ involving regions of residues Arg49–Gln52–Lys97 (TSR-EGF-1) and Thr103–Pro106 (EGF-1) may be involved in species-specific interactions with APC as they are richer in nonconservative substitution when comparing human and bovine protein S. This preliminary model helps to plan future experiments and the resulting data will be used to further validate and optimise the present structure.",
author = "Bruno Villoutreix and Olle Teleman and Bj{\"o}rn Dahlb{\"a}ck",
year = "1997",
doi = "10.1023/A:1007912929828",
language = "English",
volume = "11",
pages = "293 -- 304",
journal = "Journal of Computer-Aided Molecular Design",
issn = "0920-654X",
publisher = "Springer",
number = "3",

}

A theoretical model for the Gla-TSR-EGF-1 region of the anticoagulant cofactor protein S : From biostructural pathology to species-specific cofactor activity. / Villoutreix, Bruno; Teleman, Olle; Dahlbäck, Björn.

In: Journal of Computer-Aided Molecular Design, Vol. 11, No. 3, 1997, p. 293 - 304.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - A theoretical model for the Gla-TSR-EGF-1 region of the anticoagulant cofactor protein S

T2 - From biostructural pathology to species-specific cofactor activity

AU - Villoutreix, Bruno

AU - Teleman, Olle

AU - Dahlbäck, Björn

PY - 1997

Y1 - 1997

N2 - Protein S (PS), which functions as a species-specific anticoagulant cofactor to activated protein C (APC), is a mosaic protein that interacts with the phospholipid membrane via its γ-carboxyglutamate-rich (Gla) module. This module is followed by the thrombin-sensitive region (TSR), sensitive to thrombin cleavage, four epidermal growth factor (EGF)-like modules and a last region referred to as the sex hormone binding globulin (SHBG) domain. Of these, the TSR and the first EGF-like regions have been shown to be important for the species-specific interaction with APC. Difficulties in crystallising PS have so far hindered its study at the atomic level. Here, we report theoretical models for the Gla and EGF-1 modules of human PS constructed using prothrombin and factor X experimental structures. The TSR was built interactively. Analysis of the model linked with the large body of biochemical literature on PS and related proteins leads to suggestions that (i) the TSR stabilises the calcium-loaded Gla module through hydrophobic and ionic interactions and its conformation depends on the presence of the Gla module; (ii) the TSR does not form a calcium binding site but is protected from thrombin cleavage in the calcium-loaded form owing to short secondary structure elements and close contact with the Gla module; (iii) the PS missense mutations in this region are consistent with the structural data, except in one case which needs further investigation; and (iv) the two PS ‘faces’ involving regions of residues Arg49–Gln52–Lys97 (TSR-EGF-1) and Thr103–Pro106 (EGF-1) may be involved in species-specific interactions with APC as they are richer in nonconservative substitution when comparing human and bovine protein S. This preliminary model helps to plan future experiments and the resulting data will be used to further validate and optimise the present structure.

AB - Protein S (PS), which functions as a species-specific anticoagulant cofactor to activated protein C (APC), is a mosaic protein that interacts with the phospholipid membrane via its γ-carboxyglutamate-rich (Gla) module. This module is followed by the thrombin-sensitive region (TSR), sensitive to thrombin cleavage, four epidermal growth factor (EGF)-like modules and a last region referred to as the sex hormone binding globulin (SHBG) domain. Of these, the TSR and the first EGF-like regions have been shown to be important for the species-specific interaction with APC. Difficulties in crystallising PS have so far hindered its study at the atomic level. Here, we report theoretical models for the Gla and EGF-1 modules of human PS constructed using prothrombin and factor X experimental structures. The TSR was built interactively. Analysis of the model linked with the large body of biochemical literature on PS and related proteins leads to suggestions that (i) the TSR stabilises the calcium-loaded Gla module through hydrophobic and ionic interactions and its conformation depends on the presence of the Gla module; (ii) the TSR does not form a calcium binding site but is protected from thrombin cleavage in the calcium-loaded form owing to short secondary structure elements and close contact with the Gla module; (iii) the PS missense mutations in this region are consistent with the structural data, except in one case which needs further investigation; and (iv) the two PS ‘faces’ involving regions of residues Arg49–Gln52–Lys97 (TSR-EGF-1) and Thr103–Pro106 (EGF-1) may be involved in species-specific interactions with APC as they are richer in nonconservative substitution when comparing human and bovine protein S. This preliminary model helps to plan future experiments and the resulting data will be used to further validate and optimise the present structure.

U2 - 10.1023/A:1007912929828

DO - 10.1023/A:1007912929828

M3 - Article

VL - 11

SP - 293

EP - 304

JO - Journal of Computer-Aided Molecular Design

JF - Journal of Computer-Aided Molecular Design

SN - 0920-654X

IS - 3

ER -