View source for Apolipoprotein H

{{Infobox_gene}}
'''Apolipoprotein H''' ('''Apo-H'''), previously known as '''β<sub>2</sub>-glycoprotein I''' and '''beta-2 glycoprotein I''', is a 38 kDa multifunctional [[apolipoprotein]] that in humans is encoded by the ''APOH'' gene{{Citation needed|date=November 2015}}. One of its functions is to bind [[cardiolipin]]. When bound the structure of cardiolipin and Apo-H both undergo large changes in structure.<ref name="pmid7586693">{{cite journal |vauthors=Borchman D, Harris EN, Pierangeli SS, Lamba OP | title = Interactions and molecular structure of cardiolipin and beta 2-glycoprotein 1 (beta 2-GP1) | journal = Clin. Exp. Immunol. | volume = 102 | issue = 2 | pages = 373–8 | year = 1995 | pmid = 7586693 | doi = 10.1111/j.1365-2249.1995.tb03792.x| pmc = 1553418 }}</ref> 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).<ref name="pmid8871678">{{cite journal |vauthors=Sheng Y, Sali A, Herzog H, Lahnstein J, Krilis SA | title = 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 | journal = J. Immunol. | volume = 157 | issue = 8 | pages = 3744–51 | year = 1996 | pmid = 8871678 | doi = }}</ref>

Apo-H has a complex involvement in [[agglutination]], it appears to alter [[adenosine diphosphate]] (ADP) mediated agglutination of platelets.<ref name="pmid4082080">{{cite journal |vauthors=Nimpf J, Wurm H, Kostner GM | title = Interaction of beta 2-glycoprotein-I with human blood platelets: influence upon the ADP-induced aggregation | journal = Thromb. Haemost. | volume = 54 | issue = 2 | pages = 397–401 | year = 1985 | pmid = 4082080 | doi = }}</ref> Normally Apo-H assumes an anti-coagulation activity in serum (by inhibiting [[coagulation factors]]); however, changes in blood factors can result of a reversal of that activity.

==Inhibitory activities==
Apo-H appears to completely inhibit [[serotonin]] release by the platelets<ref name="pmid3827975">{{cite journal |vauthors=Nimpf J, Wurm H, Kostner GM | title = Beta 2-glycoprotein-I (apo-H) inhibits the release reaction of human platelets during ADP-induced aggregation | journal = Atherosclerosis | volume = 63 | issue = 2–3 | pages = 109–14 | year = 1987 | pmid = 3827975 | doi =10.1016/0021-9150(87)90110-9 }}</ref> and prevents subsequent waves of the ADP-induced aggregation. The activity of Apo-H appears to involve the binding of agglutinating, negatively charged compounds, and  inhibits agglutination by the contact activation of the intrinsic blood coagulation pathway.<ref name="pmid4052628">{{cite journal | author = Schousboe I | title = beta 2-Glycoprotein I: a plasma inhibitor of the contact activation of the intrinsic blood coagulation pathway | journal = Blood | volume = 66 | issue = 5 | pages = 1086–91 | year = 1985 | pmid = 4052628 | doi = }}</ref>  Apo-H 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 Apo-H suggesting a regulatory role of Apo-H in coagulation.<ref name="pmid3768409">{{cite journal |vauthors=Nimpf J, Bevers EM, Bomans PH | title = Prothrombinase activity of human platelets is inhibited by beta 2-glycoprotein-I | journal = Biochim. Biophys. Acta | volume = 884 | issue = 1 | pages = 142–9 | year = 1986 | pmid = 3768409 | doi = 10.1016/0304-4165(86)90237-0|display-authors=etal}}</ref>

Apo-H also inhibits the generation of [[factor Xa]] in the presence of platelets.<ref name="pmid8236146">{{cite journal |vauthors=Shi W, Chong BH, Hogg PJ, Chesterman CN | title = Anticardiolipin antibodies block the inhibition by beta 2-glycoprotein I of the factor Xa generating activity of platelets | journal = Thromb. Haemost. | volume = 70 | issue = 2 | pages = 342–5 | year = 1993 | pmid = 8236146 | doi = }}</ref> Apo-H also inhibits that activation of [[factor XII]]a.<ref name="pmid7482406">{{cite journal |vauthors=Schousboe I, Rasmussen MS | title = Synchronized inhibition of the phospholipid mediated autoactivation of factor XII in plasma by beta 2-glycoprotein I and anti-beta 2-glycoprotein I | journal = Thromb. Haemost. | volume = 73 | issue = 5 | pages = 798–804 | year = 1995 | pmid = 7482406 | doi = }}</ref>

In addition, Apo-H inhibits the activation of protein C blocking its activity on phosphatidylserine:phosphatidylcholine vesicles<ref name="pmid8227406">{{cite journal |vauthors=Keeling DM, Wilson AJ, Mackie IJ, Isenberg DA, Machin SJ | title = Role of beta 2-glycoprotein I and anti-phospholipid antibodies in activation of protein C in vitro | journal = J. Clin. Pathol. | volume = 46 | issue = 10 | pages = 908–11 | year = 1993 | pmid = 8227406 | doi =10.1136/jcp.46.10.908 | pmc = 501616 }}</ref> however once protein C is activated, Apo-H fails to inhibit activity. Since protein C is involved in [[factor V]]a degradation Apo-H indirectly inhibits the degradation of factor Va.<ref name="pmid7741146">{{cite journal |vauthors=Matsuda J, Gohchi K, Kawasugi K, Gotoh M, Saitoh N, Tsukamoto M | title = Inhibitory activity of anti-beta 2-glycoprotein I antibody on factor Va degradation by activated-protein C and its cofactor protein S | journal = Am. J. Hematol. | volume = 49 | issue = 1 | pages = 89–91 | year = 1995 | pmid = 7741146 | doi =10.1002/ajh.2830490116 }}</ref> This inhibitory activity was diminished by adding phospholipids suggesting the Apo-H inhibition of protein C is phospholipid competitive.<ref name="pmid8713779">{{cite journal |vauthors=Mori T, Takeya H, Nishioka J, Gabazza EC, Suzuki K | title = beta 2-Glycoprotein I modulates the anticoagulant activity of activated protein C on the phospholipid surface | journal = Thromb. Haemost. | volume = 75 | issue = 1 | pages = 49–55 | year = 1996 | pmid = 8713779 | doi = }}</ref> This indicates that under certain conditions Apo-H takes on a procoagulation properties.

==Pathology==
Anti-cardiolipin antibodies are found in both infectious and some systemic autoimmune diseases (eg. [[Systemic scleroderma|systemic sclerosis (scleroderma)]], [[Systemic lupus erythematosus|systemic lupus erythematosus (SLE)]]).<ref name="pmid12082318">{{cite journal|vauthors=Kumar KS, Jyothy A, Prakash MS, Rani HS, Reddy PP|year=2002|title=Beta2-glycoprotein I dependent anticardiolipin antibodies and lupus anticoagulant in patients with recurrent pregnancy loss|journal=Journal of Postgraduate Medicine|volume=48|issue=1|pages=5–10|doi=|pmid=12082318}}</ref>  One having anti-cardiolipin antibodies shows false positivity in the [[syphilis]] test as it is performed with the antigen bound to cardiolipin surface, which anti-cardiolipin antibodies can cross-react with. The activity of [[anti-cardiolipin antibodies]] in autoimmune [[antiphospholipid syndrome]] requires apolipoprotein H.<ref name="pmid2349221">{{cite journal |vauthors=McNeil HP, Simpson RJ, Chesterman CN, Krilis SA | title = Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: beta 2-glycoprotein I (apolipoprotein H) | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 87 | issue = 11 | pages = 4120–4 | year = 1990 | pmid = 2349221 | doi =10.1073/pnas.87.11.4120 | pmc = 54059 }}</ref><ref name="pmid1301967">{{cite journal |vauthors=Hunt JE, McNeil HP, Morgan GJ, Crameri RM, Krilis SA | title = A phospholipid-beta 2-glycoprotein I complex is an antigen for anticardiolipin antibodies occurring in autoimmune disease but not with infection | journal = Lupus | volume = 1 | issue = 2 | pages = 75–81 | year = 1992 | pmid = 1301967 | doi =10.1177/096120339200100204 }}</ref> The subset of antibodies that bind Apo-H and alter its activity are considered different from antibodies that bind thrombin, serum phospholipids and are called [[anti-apolipoprotein antibodies]]. In autoimmune disease, [[anti-apolipoprotein antibodies]] (Anti β<sub>2</sub> glycoprotein I antibodies) strongly associate with thrombotic forms of [[Systemic lupus erythematosus|lupus]] and [[Sclerosis (medicine)|sclerosis]].

==Sushi 2 protein domain==
{{Infobox protein family
| Symbol = Sushi_2
| Name = Sushi_2
| image = PDB 1g4g EBI.jpg
| width = 
| caption = NMR structure of the fifth domain of human beta-2-glycoprotein I
| Pfam = PF09014
| Pfam_clan =  
| InterPro = IPR015104
| SMART = 
| PROSITE = 
| MEROPS = 
| SCOP = 
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}
In [[molecular biology]], the [[protein domain]] '''Sushi 2''' is also known as the fifth protein domain of beta-2-glycoprotein-1 (b2GP-1). 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.<ref name="pmid15522884">{{cite journal|vauthors=Shi T, Giannakopoulos B, Iverson GM, Cockerill KA, Linnik MD, Krilis SA | title=Domain V of beta2-glycoprotein I binds factor XI/XIa and is cleaved at Lys317-Thr318. | journal=J Biol Chem | year= 2005 | volume= 280 | issue= 2 | pages= 907–12 | pmid=15522884 | doi=10.1074/jbc.M410291200 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15522884  }}</ref>

===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 [[turn (biochemistry)|loop]].<ref name="pmid11124037">{{cite journal |vauthors=Hoshino M, Hagihara Y, Nishii I, Yamazaki T, Kato H, Goto Y | title = Identification of the phospholipid-binding site of human beta(2)-glycoprotein I domain V by heteronuclear magnetic resonance | journal = J. Mol. Biol. | volume = 304 | issue = 5 | pages = 927–39 |date=December 2000 | pmid = 11124037 | doi = 10.1006/jmbi.2000.4243 | url = }}</ref> 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.<ref name="pmid15522884"/>

===Function===
Its exact function remains to be fully elucidated, however it is known to play an important role in the [[Binding (molecular)|binding]] of b2GP-1 to negatively charged compounds and subsequent capture for binding of anti-b2GP-1 [[antibodies]].<ref name="pmid11124037"/> Problems such as a mutation in this protein would lead to [[Antiphospholipid syndrome]] which often leads to pregnancy complications.<ref name="pmid15522884"/>

==References==
{{Reflist|2}}

==External links==
* {{MeshName|Apolipoprotein+H}}
* [https://www.mabtech.com/knowledge-center/applied-research/apolipoproteins Apolipoprotein H and Applied Research]
* {{UCSC gene info|APOH}}

{{Autoantigens}}
{{Lipoproteins}}
{{Glycoproteins}}

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[[Category:Autoimmune diseases]]
[[Category:Apolipoproteins]]
[[Category:Autoantigens]]