Apolipoprotein H Explained

β2-glycoprotein 1, also known as beta-2 glycoprotein 1 and Apolipoprotein H (Apo-H), is a 38 kDa multifunctional plasma protein that in humans is encoded by the APOH gene.[1] One of its functions is to bind cardiolipin. When bound, the structure of cardiolipin and β2-GP1 both undergo large changes in structure.[2] Within the structure of Apo-H is a stretch of positively charged amino acids (protein sequence positions 282-287), Lys-Asn-Lys-Glu-Lys-Lys, are involved in phospholipid binding (see image on right).[3]

β2-GP1 has a complex involvement in agglutination. It appears to alter adenosine diphosphate (ADP)-mediated agglutination of platelets.[4] Normally, β2-GP1 assumes an anticoagulation activity in serum (by inhibiting coagulation factors); however, changes in blood factors can result in a reversal of that activity.

Although previously referred to as apolipoprotein H, it is not present in appreciable quantities in the lipoprotein fractions, so ApoH is therefore thought to be a misnomer.[5]

Inhibitory activities

β2-GP1 appears to completely inhibit serotonin release by the platelets[6] and prevents subsequent waves of the ADP-induced aggregation. The activity of β2-GP1 appears to involve the binding of agglutinating, negatively charged compounds, and inhibits agglutination by the contact activation of the intrinsic blood coagulation pathway.[7] β2-GP1 causes a reduction of the prothrombinase binding sites on platelets and reduces the activation caused by collagen when thrombin is present at physiological serum concentrations of β2-GP1 suggesting a regulatory role of β2-GP1 in coagulation.[8]

β2-GP1 also inhibits the generation of factor Xa in the presence of platelets.[9] β2-GP1 also inhibits that activation of factor XIIa.[10]

In addition, β2-GP1 inhibits the activation of protein C blocking its activity on phosphatidylserine:phosphatidylcholine vesicles[11] however once protein C is activated, Apo-H fails to inhibit activity. Since protein C is involved in factor Va degradation Apo-H indirectly inhibits the degradation of factor Va.[12] This inhibitory activity is diminished by adding phospholipids suggesting the Apo-H inhibition of protein C is phospholipid competitive.[13] This indicates that under certain conditions Apo-H takes on procoagulation properties.

Pathology

Anti-β2-GP1 antibodies are found in both infectious and some systemic autoimmune diseases (eg. systemic lupus erythematosus (SLE)).[14] Positivity for anti-cardiolipin antibodies in diagnostic tests for autoimmune antiphospholipid syndrome requires the presence of β2-GP1in the cardiolipin extract.[15] [16] Anti-β2-GP1 antibodies are strongly associated with thrombotic forms of lupus.

Sushi 2 protein domain

Symbol:Sushi_2
Sushi_2
Pfam:PF09014
Interpro:IPR015104

In molecular biology, the protein domain Sushi 2 is also known as the fifth protein domain of beta-2 glycoprotein 1 (β2-GP1). This protein domain is only found in eukaryotes. The first four domains found in Apolipoprotein H resemble each other, however the fifth one appears to be different.[17]

Structure

This protein domain is composed of four well-defined anti-parallel beta-strands and two short alpha-helices, as well as a long highly flexible loop.[18] Additionally, the fifth protein domain appears to resemble the other four in Apolipoprotein with the exception of three internal disulfide bonds and an extra C-terminal loop.[17]

Function

Its exact function remains to be fully elucidated; however it is known to play an important role in the binding of β2-GP1 to negatively charged compounds and subsequent capture for binding of anti-β2-GP1 antibodies.[18] Development of antibodies against β2-GP1 can lead to Antiphospholipid syndrome which often leads to pregnancy complications.[17]

External links

Notes and References

  1. Web site: APOH - Beta-2-glycoprotein 1 precursor - Homo sapiens (Human) - APOH gene & protein . UniProt . 5 May 2019.
  2. Borchman D, Harris EN, Pierangeli SS, Lamba OP . Interactions and molecular structure of cardiolipin and beta 2-glycoprotein 1 (beta 2-GP1) . Clin. Exp. Immunol. . 102 . 2 . 373–8 . 1995 . 7586693 . 10.1111/j.1365-2249.1995.tb03792.x. 1553418 .
  3. Sheng Y, Sali A, Herzog H, Lahnstein J, Krilis SA . Site-directed mutagenesis of recombinant human beta 2-glycoprotein I identifies a cluster of lysine residues that are critical for phospholipid binding and anti-cardiolipin antibody activity . J. Immunol. . 157 . 8 . 3744–51 . 1996 . 10.4049/jimmunol.157.8.3744 . 8871678 . 12529388 . free .
  4. Nimpf J, Wurm H, Kostner GM . Interaction of beta 2-glycoprotein-I with human blood platelets: influence upon the ADP-induced aggregation . Thromb. Haemost. . 54 . 2 . 397–401 . 1985 . 4082080 . 10.1055/s-0038-1657748. 23669362 .
  5. Ağar C, de Groot PG, Levels JH, Marquart JA, Meijers JC . Beta2-glycoprotein I is incorrectly named apolipoprotein H . Journal of Thrombosis and Haemostasis . 7 . 1 . 235–6 . January 2009 . 19017258 . 10.1111/j.1538-7836.2008.03223.x . 43329586 . free .
  6. Nimpf J, Wurm H, Kostner GM . Beta 2-glycoprotein-I (apo-H) inhibits the release reaction of human platelets during ADP-induced aggregation . Atherosclerosis . 63 . 2–3 . 109–14 . 1987 . 3827975 . 10.1016/0021-9150(87)90110-9 .
  7. Schousboe I . beta 2-Glycoprotein I: a plasma inhibitor of the contact activation of the intrinsic blood coagulation pathway . Blood . 66 . 5 . 1086–91 . 1985 . 4052628 . 10.1182/blood.V66.5.1086.1086. free .
  8. Nimpf J, Bevers EM, Bomans PH . Prothrombinase activity of human platelets is inhibited by beta 2-glycoprotein-I . Biochim. Biophys. Acta . 884 . 1 . 142–9 . 1986 . 3768409 . 10.1016/0304-4165(86)90237-0. etal.
  9. Shi W, Chong BH, Hogg PJ, Chesterman CN . Anticardiolipin antibodies block the inhibition by beta 2-glycoprotein I of the factor Xa generating activity of platelets . Thromb. Haemost. . 70 . 2 . 342–5 . 1993 . 8236146 . 10.1055/s-0038-1649577. 35371017 .
  10. Schousboe I, Rasmussen MS . Synchronized inhibition of the phospholipid mediated autoactivation of factor XII in plasma by beta 2-glycoprotein I and anti-beta 2-glycoprotein I . Thromb. Haemost. . 73 . 5 . 798–804 . 1995 . 7482406 . 10.1055/s-0038-1653871. 89295513 .
  11. Keeling DM, Wilson AJ, Mackie IJ, Isenberg DA, Machin SJ . Role of beta 2-glycoprotein I and anti-phospholipid antibodies in activation of protein C in vitro . J. Clin. Pathol. . 46 . 10 . 908–11 . 1993 . 8227406 . 10.1136/jcp.46.10.908 . 501616 .
  12. Matsuda J, Gohchi K, Kawasugi K, Gotoh M, Saitoh N, Tsukamoto M . Inhibitory activity of anti-beta 2-glycoprotein I antibody on factor Va degradation by activated-protein C and its cofactor protein S . Am. J. Hematol. . 49 . 1 . 89–91 . 1995 . 7741146 . 10.1002/ajh.2830490116 . 42539225 .
  13. Mori T, Takeya H, Nishioka J, Gabazza EC, Suzuki K . beta 2-Glycoprotein I modulates the anticoagulant activity of activated protein C on the phospholipid surface . Thromb. Haemost. . 75 . 1 . 49–55 . 1996 . 8713779 . 10.1055/s-0038-1650220. 34123144 .
  14. Kumar KS, Jyothy A, Prakash MS, Rani HS, Reddy PP. 2002. Beta2-glycoprotein I dependent anticardiolipin antibodies and lupus anticoagulant in patients with recurrent pregnancy loss. Journal of Postgraduate Medicine. 48. 1. 5–10. 12082318.
  15. McNeil HP, Simpson RJ, Chesterman CN, Krilis SA . Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: beta 2-glycoprotein I (apolipoprotein H) . Proc. Natl. Acad. Sci. U.S.A. . 87 . 11 . 4120–4 . 1990 . 2349221 . 10.1073/pnas.87.11.4120 . 54059 . 1990PNAS...87.4120M . free .
  16. Hunt JE, McNeil HP, Morgan GJ, Crameri RM, Krilis SA . A phospholipid-beta 2-glycoprotein I complex is an antigen for anticardiolipin antibodies occurring in autoimmune disease but not with infection . Lupus . 1 . 2 . 75–81 . 1992 . 1301967 . 10.1177/096120339200100204 . 35296154 .
  17. Shi T, Giannakopoulos B, Iverson GM, Cockerill KA, Linnik MD, Krilis SA . Domain V of beta2-glycoprotein I binds factor XI/XIa and is cleaved at Lys317-Thr318. . J Biol Chem . 2005 . 280 . 2 . 907–12 . 15522884 . 10.1074/jbc.M410291200 . free .
  18. Hoshino M, Hagihara Y, Nishii I, Yamazaki T, Kato H, Goto Y . Identification of the phospholipid-binding site of human beta(2)-glycoprotein I domain V by heteronuclear magnetic resonance . J. Mol. Biol. . 304 . 5 . 927–39 . December 2000 . 11124037 . 10.1006/jmbi.2000.4243 .

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