alpha-1 acid glycoprotein

Alpha-1-acid glycoprotein (AGP) or orosomucoid (ORM) is an acute phase protein synthesized in response to pro-inflammatory cytokines early in the inflammatory response.

AGP gene expression is controlled by a combination of the major regulatory mediators – glucocorticoids and a cytokine network involving IL-1β, TNF-α, IL-6, and IL-6 related cytokines. Human AGP is a 41-43 kDa glycoprotein with single chain of 183 amino acids plus five to six highly sialylated complex-type-N-linked glycans, rendering the molecule heavily glycosylated (45%). Binding affinity and immunomodulatory activities of AGP are mostly dependent on carbohydrate composition.

Alpha-1-acid glycoprotein. Fournier T, Medjoubi-N N, Porquet D. Biochim Biophys Acta. 2000 Oct 18;1482(1-2):157-71.

tags [Proteins] [acute phase] [alpha-1-acid glycoprotein] [inflammation] [cytokine]

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alpha 1-antichymotrypsin

alpha 1-Antichymotrypsin (ACT) is an an acute phase protein synthesized in response to pro-inflammatory cytokines early in the inflammatory response.

ACT is a member of the serine proteinase inhibitor (serpin) family that inhibits neutrophilic proteinases – chymotrypsin, cathepsin G, chymases from mast cells, and elastase – protecting tissue from damage by these proteolytic enzymes. ACT is a glycoprotein found in alpha(1)-globulin region in human serum. Alpha 1-antichymotrypsin contains a reactive centre loop that interacts with cognate proteinases, resulting in loop cleavage and a major conformational change.

As an acute phase protein, ACT is active in the control of immune and inflammatory responses, and acts as a tumor marker. ACT inhibits CTL-mediated lysis (CML).

ACT has been identified as a major constituent of the neurofibrillary plaques associated with Alzheimers disease, where it probably enhances the rate of amyloid-fibril formation. Genetic data also suggests that alpha 1-antichymotrypsin is important in the pathogenesis of Alzheimer's disease.[s]

tags [Proteins] [alpha-1 antichymotrypsin] [inflammation] [cytokine] [serine protease inhibitor] [Alzheimers]

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alpha 1-antitrypsin

Alpha 1-antitrypsin or α1-antitrypsin (A1AT) or alpha-1 proteinase inhibitor (α1-PI) is an an acute phase protein synthesized in response to pro-inflammatory cytokines early in the inflammatory response.

A1AT is a 52 kDa prototypical serine protease inhibitor (serpin) that protects against enzymes released by inflammatory cells, particularly elastase, which is released from neutrophilic granules. A1AT forms covalent bonds with both elastase and trypsin, irreversibly inactivating these proteolytic enzymes.

Alpha 1-antitrypsin deficiency is a hereditary disorder in which inability to inactivate elastase and trypsin allows inflammatory tissue breakdown, causing pulmonary emphysema and hepatic cirrhosis in severe cases.

tags [Proteins] [alpha 1-antitrypsin] [inflammation] [cytokine] [serine protease inhibitor]

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alpha 2-macroglobulin

Alpha-2 macroglobulin (A2M), α-2 macroglobulin is an an acute phase protein synthesized in response to pro-inflammatory cytokines early in the inflammatory response.

A2M is a large plasma protein produced by the liver, and is a major component of the alpha-2 band in protein electrophoresis. A2M interacts and captures virtually any proteinase whether self or foreign, suggesting a function as a unique "panproteinase inhibitor." A2M also removes the active forms of the gelatinase (MMP-2 and MMP-9) from the circulation, binding to scavenger receptors on the phagocytes. In the mechanism termed "clearance of activated alpha 2-macroglobulin", ACT undergoes Ca(2+)-dependent binding to a member of the low-density lipoprotein receptor supergene family that mediates cellular uptake by endocytosis and delivery to endosomes and lysosomes. Thus, the peptide binding function of A2M allows targeting of biologically active peptides to different cell types expressing the A2M receptor. Complexes internalized through this binding may be dispatched into different pathways of endocytic/lysosomal pathways in a cell type-specific manner.[r]

A2M ratios are increased in nephrotic syndrome when the kidneys lose smaller plasma proteins (proteinuria). A common variant of α2-macroglobulin is associated with increased risk of Alzheimers disease.

 Scavenger Receptors

tags [Proteins] [alpha 2- macroglobulin] [inflammation] [cytokine] [serine protease inhibitor] [Alzheimers] [nephrotic+syndrome]

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coagulation factors

Coagulation factors participate in the coagulation cascade, which is initiated within 20 seconds of an injury to the endothelial cells that line blood vessels (primary hemostasis, acute phase reaction).

Coagulation factors are synthesized by the liver and their production increases in response to pro-inflammatory cytokines released in the acute phase early in the inflammatory response, in particular:
● factor VIII
● fibrinogen
● plasminogen
● prothrombin
● von Willebrand factor

tags [Proteins] [acute phase] [coagulation factors] [clotting cascade] [cytokine] [hemostasis]

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C-reactive protein

C-reactive protein is an acute phase protein produced by the liver within 6 hours of an acute inflammatory stimulus. Levels peak after about 50 hours.

CRP is a pentraxin protein that exhibits calcium dependant ligand binding and a distinctive flattened β-jellyroll structure. (left - image - click to enlarge) CRP is so-named because it reacts with the somatic C polysaccharide of the bacterium Streptococcus pneumoniae. Serum amyloid P component is another pentraxin, acute phase protein.

CRP binds specifically to phosphocholine moieties, conferring a host-defensive role on CRP since phosphocholine is a component of microbial polysaccharides. CRP also binds to ligands exposed on damaged cells.

CRP-phosphocholine-binding:
● activates the classical complement pathway
● acts as an opsonin ligand for phagocytosis
● neutralizes the pro-inflammatory platelet-activating factor (PAF)
● down-regulates polymorphs
CRP
● increases production of tissue-factors by monocytes
● activates smooth muscle K+ ion channels (vasodilator)
● delays apoptosis of neutrophils when the pentameric structure is lost and the molecule exists as a monomer (mCRP)

CRP is mildly elevated in: systemic lupus erythematosus, systemic sclerosis, sermatomyositis, ulcerative colitis, leukaemia, and graft-versus-host disease (GVHD).

The C-reactive protein medical test measures levels of CRP to assess acute inflammation. An association has been demonstrated between sudden cardiac death, peripheral arterial disease and hs-CRP, so serum CRP levels may correlate with cardiovascular disease risk.

tags [Proteins] [C-reactive protein] [acute phase] [classical complement pathway] [inflammation] [pentraxin]

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ferritin

Ferritin is an an acute phase protein synthesized in response to pro-inflammatory cytokines early in the inflammatory response.

Ferritin is the chief iron storage protein for both eukaryotes and prokaryotes, and is termed apoferritin when not combined with Fe(3+) ions. The globular ferritin protein complex comprises 24 subunits – hetero-oligomers of light (L) and heavy (H) chains encoded by homologous genes (vertebrates), H chains only in bacteria and plants. Free Fe is toxic, so cells employ ferritin molecules or aggregates (hemosiderin) to form protective Fe-protein complexes. Each ferritin molecule complexes around 4500 (Fe3+)ions.

Ferritin is found in most tissues, particularly in the bone marrow and reticuloendothelial system (or mononuclear phagocytic system). Serum ferritin levels are proportional to iron storage levels in humans and are employed as a part of the work-up for anemia, particurlarly iron-deficiency anemia. However, ferritin levels are increased by acute inflammation, hemochromatosis, malignancy, hyperthyroidism, Still's Disease, or hepatic disease (necrotic hepatocytes), so ferritin levels may be misleading when anemia is concomitant with these conditions.

tags [Proteins] [acute phase] [ferritin] [iron storage] [iron deficiency anemia] [inflammation] [hemochromatosis]

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fibronectin

Fibronectin (FN) is a high molecular weight, multidomain glycoprotein, comprising about 5% by weight of carbohydrate.

Fibronectin exhibits diverse recognition functions located on distinct fragments or domains, so FN can interact with a variety of macromolecules including/on :
● cytoskeleton
● extracellular matrix – collagen, glycosaminoglycans, proteoglycans, tenascin, fibulin and thrombospondin
● circulating coagulation factors – Fn is covalently incorporated into fibrin clots through the transglutaminase action of coagulation factor XIII, improving fibroblast adhesion
● fibrinolytic system
● acute phase proteins
● complement system
● cell-surface receptors on a variety of cells including fibroblasts, neurons, phagocytes and bacteria – integrins (through RGD tripeptide)
● itself, forming fibrillar entities
● small molecules such as gangliosides, sugars, and Ca ions.

Fibronectin (FN) participates in tissue repair, embryogenesis, blood clotting, and cell migration/adhesion. Cells of most tissues synthesize fibronectin. Soluble fibronectin is produced by hepatocytes and circulates, in its disulfide-bonded dimeric form, in the plasma. The soluble protomer is a compact, flexible dimer that can be converted into an insoluble, fibrillar network. The soluble-to-fibrillar conversion is a highly regulated process involving integrins and possibly other cell-surface receptors [ref] including uPAR (urokinase-type plasminogen activator receptor) [ref] and a cell-surface proteoglycan [ref].[s]

The insoluble fibronectin dimer is synthesized by fibroblasts, chondrocytes, endothelial cells, macrophages, as well as certain epithelial cells. Electron microscopic analyses of natural thin fibrils (5-18nm diameter), made by fibroblasts in culture, clearly indicate an ordered arrangement and suggest a model in which extended protomers (130nm long) are arranged end-to-end with an overlap of about 14 nm [ref]. As an extracellular adhesion molecule, FN binds to integrins and participates in wound healing.

Cell-surface receptors or fibrinogen, collagen and fibrin (as extracellular matrix proteins) facilitate the adherence of microorganisms to host tissues [ref]. The Hep-2 domain of fibronectin interacts with envelope glycoproteins on some retroviruses. Fibronectin is able to bind both the virus and cell-surface receptors, concentrating viruses on the surface of the cells, enhancing viral uptake by cells.

The structural isoforms of fibronectin arise from alternative splicing of a single gene, and possess a variable region plus three types of repeated internal regions (homologous, repeating modules I, II and III) +/- disulfide bonds.

[more] [] The Type I module of fibronectin [] The Type II module (F2) [] segment of fibronectin , four Type III modules []

tags [Proteins] [fibronectin]

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haptoglobins

Haptoglobins (Hp) are acute phase proteins synthesized in response to pro-inflammatory cytokines early in the inflammatory response.

Haptoglobins are alpha-2-globulins that remove free hemoglobin from plasma by forming a stable complex that aids in recycling of heme iron.

Haptoglobins are elevated in inflammation, malignancies (particularly with metastases to bone), trauma, surgery, steroid or androgen therapy, and diabetes.

tags [Proteins] [acute phase] [haptoglobins] [alpha-2-globulins] [inflammation] [cytokine]

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mannose-binding protein

Mannose binding protein (MBP) or mannan-binding lectin (MBL) is a member of the collectin family, and is a C−type serum lectin that participates in the innate inflammatory response in defense against a variety of bacterial, fungal and viral pathogens.

▼ acute phase : CD45 : collectins : domains CRD vs CTLD vs CARD : evolution : ficolins : inflammatory response : lectin pathway of complement activation : MBL-MASP : mutations : receptor : T-cells ▼

MBP is an acute phase protein synthesized in response to pro-inflammatory cytokines early in the inflammatory response. The receptor that recognizes CRD-carrying MBP, and structurally-related complement or lectin opsonins (collectins), is widely distributed on leukocytes, platelets, and endothelial cells.

MBP initiates the lectin branch (MBL-MASP) of the complement cascade by binding to sugars on the surfaces of microorganisms, activating two MBP-associated serine proteases (MASP-1 and MASP-2). MBP is able to specifically recognize cell surface CD45 on immature, but not mature T cells.

The lectin pathway (MBL - MASP) is homologous to the classical pathway, but utilizes opsonin, mannan-binding lectin (MBL, MBP) and ficolins rather than C1q. Binding of mannan-binding lectin to mannose residues on the pathogen's surface activates the MBL-associated serine proteases, MASP-1, MASP-2, MASP-3, which cleave C4 into C4b and C2 into C2b. As in the classical pathway, C4b and C2b bind to form the C4b•C2b C3 convertase. Ficolins are homologous to MBL and function through MASPs. Diversified ficolins are of particular importance in invertebrates, which lack the adaptive immune response that evolved some 500 million years ago in jawed vertebrates. [] C-lectin phylogenetic tree, Immune branch, Snake toxins branch, Calcium-carbohydrate binding branch []

Mutations in the gene encoding mannose binding protein may result in defective opsonization. MBP is a 53 kDa homomultimeric trimer [] ribbon structure MBP [] Human mannose binding protein CRD [] space-fill structure hMBP [] superimposition of CRD/CTLD domains of mannose binding protein C (orange), IX/X binding protein (red), lithostathine (green), human CD94 (purple) []

MBP carries the CRD domain, whose major function is calcium-dependent recognition of oligosaccharides at cell surfaces (carbohydrate-recognition domain (CRD not CARD, which is caspase recruitment domain). The C-type-lectin-like domain (CTLD) is located in a large variety of proteins and is similar to the CRD domain on C- lectins (C-lectin domain). Although CTLDs are similar to CRDs of C-lectins in sequence and structure, they serve different functions.

▲ф ф activation ф activation complement cascade : acute phase ф acute phase : CD45 : collectins ф complement system : domains CRD vs CTLD vs CARD : evolution »» Evolution : ficolins ф humoral immunity ф immune cytokines ф immune response ф inflammatory response : inflammatory response : lectin pathway of complement activation : MBL-MASP : mutations »» Mutation ф pathogens : receptor ф receptors : T-cells ф T cells ▲ф

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tags [Proteins] [mannose-binding proteins] [acute phase] [C-lectins] [collectins]

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