Apolipoprotein H

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.^[5] One of its functions is to bind cardiolipin. When bound, the structure of cardiolipin and β₂-GP1 both undergo large changes in structure.^[6] 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).^[7]

APOH
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1C1Z, 1G4F, 1G4G, 1QUB, 2KRI, 3OP8, 4JHS
Identifiers
Aliases	APOH, B2G1, B2GP1, BG, apolipoprotein H
External IDs	OMIM: 138700; MGI: 88058; HomoloGene: 26; GeneCards: APOH; OMA:APOH - orthologs
Gene location (Human) Chr. Chromosome 17 (human)[1] Band 17q24.2 Start 66,212,033 bp[1] End 66,256,525 bp[1]
Gene location (Mouse) Chr. Chromosome 11 (mouse)[2] Band 11 E1|11 71.8 cM Start 108,234,180 bp[2] End 108,305,222 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in liver right lobe of liver kidney tubule testicle islet of Langerhans gonad glomerulus metanephric glomerulus pancreatic epithelial cell body of pancreas Top expressed in left lobe of liver gallbladder fetal liver hematopoietic progenitor cell spermatid human fetus seminiferous tubule sexually immature organism proximal tubule spermatocyte right kidney More reference expression data BioGPS More reference expression data
Gene ontology Molecular function heparin binding lipoprotein lipase activator activity protein binding identical protein binding phospholipid binding lipid binding Cellular component extracellular matrix chylomicron very-low-density lipoprotein particle high-density lipoprotein particle extracellular exosome platelet dense granule lumen extracellular space cell surface extracellular region collagen-containing extracellular matrix Biological process blood coagulation, intrinsic pathway negative regulation of fibrinolysis negative regulation of blood coagulation positive regulation of lipoprotein lipase activity negative regulation of endothelial cell migration negative regulation of endothelial cell proliferation positive regulation of blood coagulation negative regulation of angiogenesis triglyceride transport plasminogen activation regulation of blood coagulation negative regulation of myeloid cell apoptotic process regulation of fibrinolysis triglyceride metabolic process negative regulation of smooth muscle cell apoptotic process platelet degranulation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 350 11818 Ensembl ENSG00000091583 ENSMUSG00000000049 UniProt P02749 Q01339 RefSeq (mRNA) NM_000042 NM_013475 RefSeq (protein) NP_000033 NP_038503 Location (UCSC) Chr 17: 66.21 – 66.26 Mb Chr 11: 108.23 – 108.31 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

β₂-GP1 has a complex involvement in agglutination. It appears to alter adenosine diphosphate (ADP)-mediated agglutination of platelets.^[8] 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.^[9]

Inhibitory activities

β₂-GP1 appears to completely inhibit serotonin release by the platelets^[10] 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.^[11] 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.^[12]

β₂-GP1 also inhibits the generation of factor Xa in the presence of platelets.^[13] β₂-GP1 also inhibits that activation of factor XIIa.^[14]

In addition, β₂-GP1 inhibits the activation of protein C blocking its activity on phosphatidylserine:phosphatidylcholine vesicles^[15] 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.^[16] This inhibitory activity is diminished by adding phospholipids suggesting the Apo-H inhibition of protein C is phospholipid competitive.^[17] 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)).^[18] Positivity for anti-cardiolipin antibodies in diagnostic tests for autoimmune antiphospholipid syndrome requires the presence of β₂-GP1in the cardiolipin extract.^[19][20] Anti-β₂-GP1 antibodies are strongly associated with thrombotic forms of lupus.

Sushi 2 protein domain

Sushi_2
NMR structure of the fifth domain of human beta-2 glycoprotein 1
Identifiers
Symbol	Sushi_2
Pfam	PF09014
InterPro	IPR015104
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

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.^[21]

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.^[22] 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.^[21]

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.^[22] Development of antibodies against β₂-GP1 can lead to Antiphospholipid syndrome which often leads to pregnancy complications.^[21]