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Three-dimensional model of the SHBG-like region of anticoagulant protein S: New structure-function insights

Villoutreix, Bruno O.; Dahlbäck, Björn LU ; Borgel, Delphine; Gandrille, Sophie and Muller, Yves A. (2001) In Proteins 43(2). p.203-216
Abstract
Protein S (PS) is a vitamin K-dependent glycoprotein that consists of several modules including a C-terminal sex hormone-binding globulin (SHBG)-like domain that has been subdivided into two laminin LG-type domains, The SHBG-like region of PS is known to bind to a complement regulator molecule, C4b-binding protein (C4BP), coagulation factor Va (FVa) and receptor tyrosine kinases. Inherited PS deficiency has been associated with thromboembolic disease, Yet, study of the mechanisms by which the SI-IBG-like region of PS serves its essential functions has so far been hampered because of the lack of structural information. Recently, the three-dimensional (3D) structure of LG domains from plasma SHBG, laminin and neurexin have been reported and... (More)
Protein S (PS) is a vitamin K-dependent glycoprotein that consists of several modules including a C-terminal sex hormone-binding globulin (SHBG)-like domain that has been subdivided into two laminin LG-type domains, The SHBG-like region of PS is known to bind to a complement regulator molecule, C4b-binding protein (C4BP), coagulation factor Va (FVa) and receptor tyrosine kinases. Inherited PS deficiency has been associated with thromboembolic disease, Yet, study of the mechanisms by which the SI-IBG-like region of PS serves its essential functions has so far been hampered because of the lack of structural information. Recently, the three-dimensional (3D) structure of LG domains from plasma SHBG, laminin and neurexin have been reported and were found related to the pentraxin family, We used these X-ray structures to build homology models of the SHBG like region of human PS, We then analyzed previously reported experimental/clinical data in the light of the predicted structures. A potential calcium-binding site is found in the first LG domain of PS and D292 could play a role in this process, This region is close to the interface between the two LG domains and is also surrounded by segments that have been suggested by synthetic peptide studies to be important for C4BP or FVa binding. The 39 point mutations linked to PS deficiencies or reported as neutral variants were rationalized in the 3D structure. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
protein modeling, blood coagulation, thrombosis
in
Proteins
volume
43
issue
2
pages
203 - 216
publisher
John Wiley & Sons
external identifiers
  • wos:000167637800013
  • scopus:0035342451
ISSN
0887-3585
DOI
10.1002/1097-0134(20010501)43:2<203::AID-PROT1031>3.0.CO;2-W
language
English
LU publication?
yes
id
c214013b-319d-4cf6-a280-f274fa4366ee (old id 1119412)
date added to LUP
2008-07-17 09:59:16
date last changed
2018-05-29 10:38:04
@article{c214013b-319d-4cf6-a280-f274fa4366ee,
  abstract     = {Protein S (PS) is a vitamin K-dependent glycoprotein that consists of several modules including a C-terminal sex hormone-binding globulin (SHBG)-like domain that has been subdivided into two laminin LG-type domains, The SHBG-like region of PS is known to bind to a complement regulator molecule, C4b-binding protein (C4BP), coagulation factor Va (FVa) and receptor tyrosine kinases. Inherited PS deficiency has been associated with thromboembolic disease, Yet, study of the mechanisms by which the SI-IBG-like region of PS serves its essential functions has so far been hampered because of the lack of structural information. Recently, the three-dimensional (3D) structure of LG domains from plasma SHBG, laminin and neurexin have been reported and were found related to the pentraxin family, We used these X-ray structures to build homology models of the SHBG like region of human PS, We then analyzed previously reported experimental/clinical data in the light of the predicted structures. A potential calcium-binding site is found in the first LG domain of PS and D292 could play a role in this process, This region is close to the interface between the two LG domains and is also surrounded by segments that have been suggested by synthetic peptide studies to be important for C4BP or FVa binding. The 39 point mutations linked to PS deficiencies or reported as neutral variants were rationalized in the 3D structure.},
  author       = {Villoutreix, Bruno O. and Dahlbäck, Björn and Borgel, Delphine and Gandrille, Sophie and Muller, Yves A.},
  issn         = {0887-3585},
  keyword      = {protein modeling,blood coagulation,thrombosis},
  language     = {eng},
  number       = {2},
  pages        = {203--216},
  publisher    = {John Wiley & Sons},
  series       = {Proteins},
  title        = {Three-dimensional model of the SHBG-like region of anticoagulant protein S: New structure-function insights},
  url          = {http://dx.doi.org/10.1002/1097-0134(20010501)43:2<203::AID-PROT1031>3.0.CO;2-W},
  volume       = {43},
  year         = {2001},
}