Crystal structures of the membrane-binding C2 domain of human coagulation factor V

Sandra Macedo-Ribeiro, Wolfram Bode, Robert Huber, Mary Ann Quinn-Allen, Suhng Wook Kim, Thomas L. Ortel, Gleb P. Bourenkow, Hans D. Bartunik, Milton T. Stubbs, William H. Kane, Pablo Fuentes-Prior

Research output: Contribution to journalArticle

206 Citations (Scopus)

Abstract

Rapid and controlled clot formation is achieved through sequential activation of circulating serine proteinase precursors on phosphatidylserine- rich procoagulant membranes of activated platelets and endothelial cells. The homologous complexes Xase and prothrombinase, each consisting of an active proteinase and a non-enzymatic cofactor, perform critical steps within this coagulation cascade. The activated cofactors VIIIa and Va, highly specific for their cognate proteinases, are each derived from precursors with the same A1-A2-B-A3-C1-C2 architecture. Membrane binding is mediated by the C2 domains of both cofactors. Here we report two crystal structures of the C2 domain of human factor Va. The conserved β-barrel framework provides a scaffold for three protruding loops, one of which adopts markedly different conformations in the two crystal forms. We propose a mechanism of calcium-independent, stereospecific binding of factors Va and VIIIa to phospholipid membranes on the basis of (1) immersion of hydrophobic residues at the apices of these loops in the apolar membrane core; (2) specific interactions with phosphatidylserine head groups in the groove enclosed by these loops; and (3) favourable electrostatic contacts of basic side chains with negatively charged membrane phosphate groups.

Original languageEnglish
Pages (from-to)434-439
Number of pages6
JournalNature
Volume402
Issue number6760
DOIs
Publication statusPublished - 1999 Nov 25
Externally publishedYes

Fingerprint

Factor V
Membranes
Phosphatidylserines
cancer procoagulant
Factor VIIIa
Factor Va
Serine Proteases
Immersion
Static Electricity
varespladib methyl
Phospholipids
Peptide Hydrolases
Blood Platelets
Endothelial Cells
Phosphates
C2 Domains
Calcium

ASJC Scopus subject areas

  • General

Cite this

Macedo-Ribeiro, S., Bode, W., Huber, R., Quinn-Allen, M. A., Kim, S. W., Ortel, T. L., ... Fuentes-Prior, P. (1999). Crystal structures of the membrane-binding C2 domain of human coagulation factor V. Nature, 402(6760), 434-439. https://doi.org/10.1038/46594

Crystal structures of the membrane-binding C2 domain of human coagulation factor V. / Macedo-Ribeiro, Sandra; Bode, Wolfram; Huber, Robert; Quinn-Allen, Mary Ann; Kim, Suhng Wook; Ortel, Thomas L.; Bourenkow, Gleb P.; Bartunik, Hans D.; Stubbs, Milton T.; Kane, William H.; Fuentes-Prior, Pablo.

In: Nature, Vol. 402, No. 6760, 25.11.1999, p. 434-439.

Research output: Contribution to journalArticle

Macedo-Ribeiro, S, Bode, W, Huber, R, Quinn-Allen, MA, Kim, SW, Ortel, TL, Bourenkow, GP, Bartunik, HD, Stubbs, MT, Kane, WH & Fuentes-Prior, P 1999, 'Crystal structures of the membrane-binding C2 domain of human coagulation factor V', Nature, vol. 402, no. 6760, pp. 434-439. https://doi.org/10.1038/46594
Macedo-Ribeiro S, Bode W, Huber R, Quinn-Allen MA, Kim SW, Ortel TL et al. Crystal structures of the membrane-binding C2 domain of human coagulation factor V. Nature. 1999 Nov 25;402(6760):434-439. https://doi.org/10.1038/46594
Macedo-Ribeiro, Sandra ; Bode, Wolfram ; Huber, Robert ; Quinn-Allen, Mary Ann ; Kim, Suhng Wook ; Ortel, Thomas L. ; Bourenkow, Gleb P. ; Bartunik, Hans D. ; Stubbs, Milton T. ; Kane, William H. ; Fuentes-Prior, Pablo. / Crystal structures of the membrane-binding C2 domain of human coagulation factor V. In: Nature. 1999 ; Vol. 402, No. 6760. pp. 434-439.
@article{0ede5cc87e524907956c10f88dd0be47,
title = "Crystal structures of the membrane-binding C2 domain of human coagulation factor V",
abstract = "Rapid and controlled clot formation is achieved through sequential activation of circulating serine proteinase precursors on phosphatidylserine- rich procoagulant membranes of activated platelets and endothelial cells. The homologous complexes Xase and prothrombinase, each consisting of an active proteinase and a non-enzymatic cofactor, perform critical steps within this coagulation cascade. The activated cofactors VIIIa and Va, highly specific for their cognate proteinases, are each derived from precursors with the same A1-A2-B-A3-C1-C2 architecture. Membrane binding is mediated by the C2 domains of both cofactors. Here we report two crystal structures of the C2 domain of human factor Va. The conserved β-barrel framework provides a scaffold for three protruding loops, one of which adopts markedly different conformations in the two crystal forms. We propose a mechanism of calcium-independent, stereospecific binding of factors Va and VIIIa to phospholipid membranes on the basis of (1) immersion of hydrophobic residues at the apices of these loops in the apolar membrane core; (2) specific interactions with phosphatidylserine head groups in the groove enclosed by these loops; and (3) favourable electrostatic contacts of basic side chains with negatively charged membrane phosphate groups.",
author = "Sandra Macedo-Ribeiro and Wolfram Bode and Robert Huber and Quinn-Allen, {Mary Ann} and Kim, {Suhng Wook} and Ortel, {Thomas L.} and Bourenkow, {Gleb P.} and Bartunik, {Hans D.} and Stubbs, {Milton T.} and Kane, {William H.} and Pablo Fuentes-Prior",
year = "1999",
month = "11",
day = "25",
doi = "10.1038/46594",
language = "English",
volume = "402",
pages = "434--439",
journal = "Nature Cell Biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "6760",

}

TY - JOUR

T1 - Crystal structures of the membrane-binding C2 domain of human coagulation factor V

AU - Macedo-Ribeiro, Sandra

AU - Bode, Wolfram

AU - Huber, Robert

AU - Quinn-Allen, Mary Ann

AU - Kim, Suhng Wook

AU - Ortel, Thomas L.

AU - Bourenkow, Gleb P.

AU - Bartunik, Hans D.

AU - Stubbs, Milton T.

AU - Kane, William H.

AU - Fuentes-Prior, Pablo

PY - 1999/11/25

Y1 - 1999/11/25

N2 - Rapid and controlled clot formation is achieved through sequential activation of circulating serine proteinase precursors on phosphatidylserine- rich procoagulant membranes of activated platelets and endothelial cells. The homologous complexes Xase and prothrombinase, each consisting of an active proteinase and a non-enzymatic cofactor, perform critical steps within this coagulation cascade. The activated cofactors VIIIa and Va, highly specific for their cognate proteinases, are each derived from precursors with the same A1-A2-B-A3-C1-C2 architecture. Membrane binding is mediated by the C2 domains of both cofactors. Here we report two crystal structures of the C2 domain of human factor Va. The conserved β-barrel framework provides a scaffold for three protruding loops, one of which adopts markedly different conformations in the two crystal forms. We propose a mechanism of calcium-independent, stereospecific binding of factors Va and VIIIa to phospholipid membranes on the basis of (1) immersion of hydrophobic residues at the apices of these loops in the apolar membrane core; (2) specific interactions with phosphatidylserine head groups in the groove enclosed by these loops; and (3) favourable electrostatic contacts of basic side chains with negatively charged membrane phosphate groups.

AB - Rapid and controlled clot formation is achieved through sequential activation of circulating serine proteinase precursors on phosphatidylserine- rich procoagulant membranes of activated platelets and endothelial cells. The homologous complexes Xase and prothrombinase, each consisting of an active proteinase and a non-enzymatic cofactor, perform critical steps within this coagulation cascade. The activated cofactors VIIIa and Va, highly specific for their cognate proteinases, are each derived from precursors with the same A1-A2-B-A3-C1-C2 architecture. Membrane binding is mediated by the C2 domains of both cofactors. Here we report two crystal structures of the C2 domain of human factor Va. The conserved β-barrel framework provides a scaffold for three protruding loops, one of which adopts markedly different conformations in the two crystal forms. We propose a mechanism of calcium-independent, stereospecific binding of factors Va and VIIIa to phospholipid membranes on the basis of (1) immersion of hydrophobic residues at the apices of these loops in the apolar membrane core; (2) specific interactions with phosphatidylserine head groups in the groove enclosed by these loops; and (3) favourable electrostatic contacts of basic side chains with negatively charged membrane phosphate groups.

UR - http://www.scopus.com/inward/record.url?scp=0033604610&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033604610&partnerID=8YFLogxK

U2 - 10.1038/46594

DO - 10.1038/46594

M3 - Article

C2 - 10586886

AN - SCOPUS:0033604610

VL - 402

SP - 434

EP - 439

JO - Nature Cell Biology

JF - Nature Cell Biology

SN - 1465-7392

IS - 6760

ER -