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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domains

A binding domain is that sequence of amino acids in a protein/protein family to which a specific ligand binds. As such, domains are vital to a protein's or enzyme's function. A structural domain is a self-stabilizing structural element that may fold independently of the rest of the protein chain.

Specific examples of domains:
● cadherin repeats
● carbohydrate-recognition domain (CRD)
● caspase recruiting domains, CARD domains
● C-lectin domain (CRD)
● C-type-lectin-like domain (CTLD)
● death domain (DD), death effector domain (DED) binds adaptor protein FADD (Fas-Associated Death Domain)
● EF-hand domains
● kringle domains
● pleckstrin homology (PH) domain family
● SH2 domain - Src homology 2 domain = p-Tyr recognition domains
● zinc finger DNA binding domains

Others (on Wiki) Arginine Finger, Armadillo repeats, Basic Leucine zipper domain (bZIP domain), Phosphotyrosine-binding domain (PTB)

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granulysin

Granulysin is a 74-aa basic protein released from human cytolytic T lymphocytes (CTL, Tc) and natural killer cells (NK).

'The five-helical bundle of granulysin resembles other "saposin folds" (such as NK-lysin). Positive charges distribute in a ring around the granulysin molecule, and one face has net positive charge. Sulfate ions bind near the segment of the molecule identified as most membrane-lytic and of highest hydrophobic moment. The ion locations may indicate granulysin's orientation of initial approach towards the membrane. The crystal packing reveals one way to pack a sheet of granulysin molecules at the cell surface for a concerted lysis effort. The energy of binding granulysin charges to the bacterial membrane could drive the subsequent lytic processes. The loosely packed core facilitates a hinge or scissors motion towards exposure of hydrophobic surface that we propose tunnels the granulysin into the fracturing target membrane.'[pm] Granulysin crystal structure and a structure-derived lytic mechanism. Anderson DH, Sawaya MR, Cascio D, Ernst W, Modlin R, Krensky A, Eisenberg D. J Mol Biol. 2003 Jan 10;325(2):355-65.

tags [Proteins] [granulysin] [killer cells] [saposin folds]

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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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