Structural basis of membrane binding by Gla domains of vitamin K-dependent proteins.
In a calcium-dependent interaction critical for blood coagulation, vitamin K-dependent blood coagulation proteins bind cell membranes containing phosphatidylserine via gamma-carboxyglutamic acid-rich (Gla) domains. Gla domain-mediated protein-membrane interaction is required for generation of thrombin, the terminal enzyme in the coagulation cascade, on a physiologic time scale. We determined by X-ray crystallography and NMR spectroscopy the lysophosphatidylserine-binding site in the bovine prothrombin Gla domain. The serine head group binds Gla domain-bound calcium ions and Gla residues 17 and 21, fixed elements of the Gla domain fold, predicting the structural basis for phosphatidylserine specificity among Gla domains. Gla domains provide a unique mechanism for protein-phospholipid membrane interaction. Increasingly Gla domains are being identified in proteins unrelated to blood coagulation. Thus, this membrane-binding mechanism may be important in other physiologic processes.
Huang
Mingdong
M
Center for Hemostasis and Thrombosis Research, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
Rigby
Alan C
AC
Morelli
Xavier
X
Grant
Marianne A
MA
Huang
Guiqing
G
Furie
Bruce
B
Seaton
Barbara
B
Furie
Barbara C
BC
D015055:1-Carboxyglutamic Acid / Q000737:chemistry*; D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine / Q000737:chemistry; D001665:Binding Sites; D001777:Blood Coagulation; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D002462:Cell Membrane / Q000378:metabolism*; D018360:Crystallography, X-Ray; D007477:Ions; D008246:Lysophospholipids / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011516:Prothrombin / Q000737:chemistry; D014812:Vitamin K / Q000737:chemistry*
D007477:Ions; D008246:Lysophospholipids; D010455:Peptides; C025059:lysophosphatidylserine; D014812:Vitamin K; D015055:1-Carboxyglutamic Acid; D011516:Prothrombin; D001120:Arginine; D002118:Calcium