β
2-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. One of its functions is to bind
cardiolipin. When bound, the structure of cardiolipin and β
2-GP1 both undergo large changes in structure.
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
Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...
binding (see image on right).
β
2-GP1 has a complex involvement in
agglutination
In linguistics, agglutination is a morphological process in which words are formed by stringing together morphemes, each of which corresponds to a single syntactic feature. Languages that use agglutination widely are called agglutinative lang ...
. It appears to alter
adenosine diphosphate
Adenosine diphosphate (ADP), also known as adenosine pyrophosphate (APP), is an important organic compound in metabolism and is essential to the flow of energy in living cells. ADP consists of three important structural components: a sugar backbon ...
(ADP)-mediated agglutination of platelets.
Normally, β
2-GP1 assumes an anticoagulation activity in serum (by inhibiting
coagulation factors
Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism o ...
); 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.
Inhibitory activities
β
2-GP1 appears to completely inhibit
serotonin
Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
release by the platelets
and prevents subsequent waves of the ADP-induced aggregation. The activity of β
2-GP1 appears to involve the binding of agglutinating, negatively charged compounds, and inhibits agglutination by the contact activation of the intrinsic blood coagulation pathway.
β
2-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 β
2-GP1 suggesting a regulatory role of β
2-GP1 in coagulation.
β
2-GP1 also inhibits the generation of
factor Xa
Factor X, also known by the eponym Stuart–Prower factor, is an enzyme () of the coagulation cascade. It is a serine endopeptidase (protease group S1, PA clan). Factor X is synthesized in the liver and requires vitamin K for its synthesis.
Fa ...
in the presence of platelets.
β
2-GP1 also inhibits that activation of
factor XII
Coagulation factor XII, also known as Hageman factor, is a plasma protein. It is the zymogen form of factor XIIa, an enzyme () of the serine protease (or serine endopeptidase) class. In humans, factor XII is encoded by the ''F12'' gene.
Struc ...
a.
In addition, β
2-GP1 inhibits the activation of protein C blocking its activity on phosphatidylserine:phosphatidylcholine vesicles
however once protein C is activated, Apo-H fails to inhibit activity. Since protein C is involved in
factor V
Factor V (pronounced factor five) is a protein of the coagulation system, rarely referred to as proaccelerin or labile factor. In contrast to most other coagulation factors, it is not enzymatically active but functions as a cofactor. Deficienc ...
a degradation Apo-H indirectly inhibits the degradation of factor Va.
This inhibitory activity is diminished by adding phospholipids suggesting the Apo-H inhibition of protein C is phospholipid competitive.
This indicates that under certain conditions Apo-H takes on procoagulation properties.
Pathology
Anti-β
2-GP1 antibodies are found in both infectious and some systemic autoimmune diseases (eg.
systemic lupus erythematosus (SLE)
Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Comm ...
).
Positivity for
anti-cardiolipin antibodies
Anti-cardiolipin antibodies (ACA) are antibodies often directed against cardiolipin and found in several diseases, including syphilis, antiphospholipid syndrome, livedoid vasculitis, vertebrobasilar insufficiency, Behçet's syndrome, idiopathic ...
in diagnostic tests for autoimmune
antiphospholipid syndrome
Antiphospholipid syndrome, or antiphospholipid antibody syndrome (APS or APLS), is an autoimmune, hypercoagulable state caused by antiphospholipid antibodies. APS provokes blood clots (thrombosis) in both arteries and veins as well as pregnancy- ...
requires the presence of β
2-GP1in the cardiolipin extract.
Anti-β
2-GP1 antibodies are strongly associated with thrombotic forms of
lupus
Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Comm ...
.
Sushi 2 protein domain
In
molecular biology
Molecular biology is the branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions. The study of chemical and physi ...
, the
protein domain
In molecular biology, a protein domain is a region of a protein's polypeptide chain that is self-stabilizing and that folds independently from the rest. Each domain forms a compact folded three-dimensional structure. Many proteins consist of s ...
Sushi 2 is also known as the fifth protein domain of beta-2 glycoprotein 1 (β
2-GP1). This protein domain is only found in
eukaryotes
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
. The first four domains found in Apolipoprotein H resemble each other, however the fifth one appears to be different.
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
Loop or LOOP may refer to:
Brands and enterprises
* Loop (mobile), a Bulgarian virtual network operator and co-founder of Loop Live
* Loop, clothing, a company founded by Carlos Vasquez in the 1990s and worn by Digable Planets
* Loop Mobile, an ...
.
Additionally, the fifth protein domain appears to resemble the other four in Apolipoprotein with the exception of three internal
disulfide bonds
In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...
and an extra
C-terminal
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
loop.
Function
Its exact function remains to be fully elucidated; however it is known to play an important role in the
binding of β
2-GP1 to negatively charged compounds and subsequent capture for binding of anti-β
2-GP1
antibodies
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
.
Development of antibodies against β
2-GP1 can lead to
Antiphospholipid syndrome
Antiphospholipid syndrome, or antiphospholipid antibody syndrome (APS or APLS), is an autoimmune, hypercoagulable state caused by antiphospholipid antibodies. APS provokes blood clots (thrombosis) in both arteries and veins as well as pregnancy- ...
which often leads to pregnancy complications.
References
External links
*
Apolipoprotein H and Applied Research*
PDBe-KBprovides an overview of all the structure information available in the PDB for Human Apolipoprotein H (B2G1)
{{Glycoproteins
Autoimmune diseases
Apolipoproteins
Autoantigens