PMID- 11711550
OWN - NLM
STAT- MEDLINE
DCOM- 20020225
LR  - 20220331
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 277
IP  - 4
DP  - 2002 Jan 25
TI  - Heparin inhibits the binding of beta 2-glycoprotein I to phospholipids and 
      promotes the plasmin-mediated inactivation of this blood protein. Elucidation of 
      the consequences of the two biological events in patients with the 
      anti-phospholipid syndrome.
PG  - 2644-9
AB  - The phospholipid-binding plasma protein beta2-glycoprotein I (beta2-GPI) is the 
      primary antigen recognized by the circulating autoantibodies in patients with the 
      "anti-phospholipid syndrome" (APS). Although heparin is routinely used in the 
      treatment and prophylaxis of APS patients, the primary heparin-binding site 
      within beta2-GPI has not been identified. More importantly, how heparin exerts 
      its beneficial effects in vivo in APS patients has not been deduced at the 
      molecular level. Using an expression/site-directed mutagenesis approach, we now 
      show that the positively charged site that resides in the first domain of 
      beta2-GPI is not the primary heparin-binding site. Rather it is the second 
      positively charged site located within the fifth domain of the protein that also 
      binds to phospholipids. Lys(284), Lys(286), and Lys(287) in this domain are 
      essential for the interaction of beta2-GPI with heparin. These data indicate that 
      beta2-GPI binds to heparin in a relatively specific manner even though the 
      affinity for the interaction is rather low. Lys(317) resides in the center of the 
      high affinity phospholipid-binding site. Surprisingly, heparin at concentrations 
      that can be achieved in vivo during anticoagulation therapy greatly enhances the 
      plasmin-mediated cleavage of the Lys(317)-Thr(318) site in beta2-GPI. Because the 
      cleaved form cannot bind to phospholipids effectively, the combined actions of 
      heparin and plasmin result in a diminished ability of beta2-GPI to recognize 
      phospholipids. This, in turn, decreases the prothrombotic activity of the 
      endogenous circulating anti-beta2-GPI antibodies in the patients. Thus, heparin 
      exerts its beneficial effects in APS patients by at least two distinct 
      mechanisms.
FAU - Guerin, Jan
AU  - Guerin J
AD  - Department of Immunology, Division of Medicine, University of New South Wales, 
      St. George Hospital, Sydney, New South Wales 2217, Australia.
FAU - Sheng, Yonghua
AU  - Sheng Y
FAU - Reddel, Stephen
AU  - Reddel S
FAU - Iverson, G Michael
AU  - Iverson GM
FAU - Chapman, Michael G
AU  - Chapman MG
FAU - Krilis, Steven A
AU  - Krilis SA
LA  - eng
PT  - Journal Article
DEP - 20011115
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Anticoagulants)
RN  - 0 (Cardiolipins)
RN  - 0 (Glycoproteins)
RN  - 0 (Haptoglobins)
RN  - 0 (Peptides)
RN  - 0 (Phospholipids)
RN  - 0 (beta 2-Glycoprotein I)
RN  - 9005-49-6 (Heparin)
RN  - EC 3.4.21.7 (Fibrinolysin)
RN  - K3Z4F929H6 (Lysine)
SB  - IM
MH  - Anticoagulants/chemistry/metabolism
MH  - Antiphospholipid Syndrome/*genetics/*metabolism
MH  - Binding Sites
MH  - Binding, Competitive
MH  - Cardiolipins/chemistry
MH  - Dose-Response Relationship, Drug
MH  - Electrophoresis, Polyacrylamide Gel
MH  - Fibrinolysin/chemistry/*metabolism
MH  - Glycoproteins/*chemistry/*metabolism
MH  - Haptoglobins/chemistry
MH  - Heparin/chemistry/metabolism/*pharmacology
MH  - Humans
MH  - Lysine/chemistry
MH  - Models, Biological
MH  - Mutagenesis, Site-Directed
MH  - Mutation
MH  - Peptides/chemistry
MH  - Phospholipids/metabolism
MH  - Protein Binding
MH  - Protein Structure, Tertiary
MH  - Time Factors
MH  - beta 2-Glycoprotein I
EDAT- 2001/11/17 10:00
MHDA- 2002/02/28 10:01
CRDT- 2001/11/17 10:00
PHST- 2001/11/17 10:00 [pubmed]
PHST- 2002/02/28 10:01 [medline]
PHST- 2001/11/17 10:00 [entrez]
AID - S0021-9258(20)87713-8 [pii]
AID - 10.1074/jbc.M110176200 [doi]
PST - ppublish
SO  - J Biol Chem. 2002 Jan 25;277(4):2644-9. doi: 10.1074/jbc.M110176200. Epub 2001 
      Nov 15.