PTX3
Encyclopedia
Pentraxin-related protein PTX3 also known as TNF-inducible gene 14 protein (TSG-14) is a protein
that in humans is encoded by the PTX3 gene
.
Pentraxin 3 (ptx3) is a member of the pentraxin superfamily. This super family characterized by cyclic multimeric structure.
PTX3 is rapidly produced and released by several cell types, in particular by mononuclear phagocytes, dendritic cells (DCs), fibroblasts and endothelial cells in response to primary inflammatory signals [e.g., toll-like receptor
(TLR) engagement, TNFα, IL-1β
]. PTX3 binds with high affinity to the complement component C1q
, the extracellular matrix component TNFα induced protein 6 (TNFAIP6; also called TNF-stimulated gene 6, TSG-6) and selected microorganisms, including Aspergillus fumigatus
and Pseudomonas aeruginosa
.
PTX3 activates the classical pathway of complement activation and facilitates pathogen recognition by macrophages and DCs.
The transcribed PTX3 protein is 381 amino acids long, has a predicted molecular weight of 40,165 Da
and consists of a carboxy-terminal 203 amino acid
long pentraxin domain coupled with an amino-terminal 178 amino acid long domain unrelated to other known proteins. The PTX3 carboxy-terminal domain contains a canonical pentraxin signature and two conserved cysteine
s (Cys-210 and Cys-271), and shares 57% conserved and 17% identical amino acids with short pentraxins. The presence of an amino-linked glycosylation
site in the carboxy-terminal domain at Asn
-220 accounts for the higher molecular weight observed in SDS–PAGE
under reducing conditions (45 kDa as opposed to the predicted 40 kDa). Under native conditions PTX3 protomers are assembled to form multimers. The crystal structure of PTX3 has not been determined yet, however according to modeling
, the PTX3 pentraxin domain well-accommodates on the tertiary fold of SAP
, with almost all of the β-strands
and the α-helical
segments conserved.
, sepsis
and other inflammatory and infectious conditions, correlating with the severity of the disease. Under these conditions, PTX3 is a rapid marker for primary local activation of innate immunity and inflammation.
, thereby inhibiting their recognition by DCs . Binding occurs late in the apoptotic process and enhances cytokine production by DCs. In addition, preincubation of apoptotic cells with PTX3 enhances C1q
binding and C3 deposition on the cell surface, suggesting a role for PTX3 in the complement-mediated clearance of apoptotic cells. Moreover, in the presence of dying cells, PTX3 restricts the cross presentation of antigens derived from dying cells. These results suggest that PTX3 has a dual role: protection against pathogens and control of autoimmunity.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the PTX3 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Pentraxin 3 (ptx3) is a member of the pentraxin superfamily. This super family characterized by cyclic multimeric structure.
PTX3 is rapidly produced and released by several cell types, in particular by mononuclear phagocytes, dendritic cells (DCs), fibroblasts and endothelial cells in response to primary inflammatory signals [e.g., toll-like receptor
Toll-like receptor
Toll-like receptors are a class of proteins that play a key role in the innate immune system. They are single, membrane-spanning, non-catalytic receptors that recognize structurally conserved molecules derived from microbes...
(TLR) engagement, TNFα, IL-1β
IL-1
IL-1 may refer to:* Interleukin 1, a protein* Illinois' 1st congressional district* Illinois Route 1* Building 1 of Infinite Loop , the Headquarters of Apple Inc....
]. PTX3 binds with high affinity to the complement component C1q
C1Q complex
The C1q complex is potentially multivalent for attachment to the complement fixation sites of immunoglobulin.The sites are on the CH2 domain of IgG and, it is thought, on the CH4 domain of IgM....
, the extracellular matrix component TNFα induced protein 6 (TNFAIP6; also called TNF-stimulated gene 6, TSG-6) and selected microorganisms, including Aspergillus fumigatus
Aspergillus fumigatus
Aspergillus fumigatus is a fungus of the genus Aspergillus, and is one of the most common Aspergillus species to cause disease in individuals with an immunodeficiency....
and Pseudomonas aeruginosa
Pseudomonas aeruginosa
Pseudomonas aeruginosa is a common bacterium that can cause disease in animals, including humans. It is found in soil, water, skin flora, and most man-made environments throughout the world. It thrives not only in normal atmospheres, but also in hypoxic atmospheres, and has, thus, colonized many...
.
PTX3 activates the classical pathway of complement activation and facilitates pathogen recognition by macrophages and DCs.
Structure
Human and murine PTX3, localized in the synthenic region of chromosome 3 (q24-28), are highly conserved, sharing 82% identical and 92% conserved amino acids. The human PTX3 gene is organized into three exons coding for the leader peptide (which is cleaved from the mature protein), the amino-terminal domain and the pentraxin domain of the protein.The transcribed PTX3 protein is 381 amino acids long, has a predicted molecular weight of 40,165 Da
Atomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...
and consists of a carboxy-terminal 203 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
long pentraxin domain coupled with an amino-terminal 178 amino acid long domain unrelated to other known proteins. The PTX3 carboxy-terminal domain contains a canonical pentraxin signature and two conserved cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
s (Cys-210 and Cys-271), and shares 57% conserved and 17% identical amino acids with short pentraxins. The presence of an amino-linked glycosylation
Glycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
site in the carboxy-terminal domain at Asn
Asparagine
Asparagine is one of the 20 most common natural amino acids on Earth. It has carboxamide as the side-chain's functional group. It is not an essential amino acid...
-220 accounts for the higher molecular weight observed in SDS–PAGE
SDS-PAGE
SDS-PAGE, sodium dodecyl sulfate polyacrylamide gel electrophoresis, describes a collection of related techniques widely used in biochemistry, forensics, genetics and molecular biology to separate proteins according to their electrophoretic mobility...
under reducing conditions (45 kDa as opposed to the predicted 40 kDa). Under native conditions PTX3 protomers are assembled to form multimers. The crystal structure of PTX3 has not been determined yet, however according to modeling
Homology modeling
Homology modeling, also known as comparative modeling of protein refers to constructing an atomic-resolution model of the "target" protein from its amino acid sequence and an experimental three-dimensional structure of a related homologous protein...
, the PTX3 pentraxin domain well-accommodates on the tertiary fold of SAP
Serum Amyloid P component
Amyloid P component, serum is the identical serum form of amyloid P component , a 25kDa pentameric protein first identified as the pentagonal constituent of in vivo pathological deposits called "amyloid"...
, with almost all of the β-strands
Beta sheet
The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...
and the α-helical
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
segments conserved.
PTX3 in blood
PTX3 behaves as an acute phase response protein, as the blood levels of PTX3, low in normal conditions (about 25 ng/mL in the mouse, < 2 ng/mL in humans), increase rapidly (peaking at 6–8 h after induction) and dramatically (200–800 ng/mL) during endotoxic shockSeptic shock
Septic shock is a medical emergency caused by decreased tissue perfusion and oxygen delivery as a result of severe infection and sepsis, though the microbe may be systemic or localized to a particular site. It can cause multiple organ dysfunction syndrome and death...
, sepsis
Sepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
and other inflammatory and infectious conditions, correlating with the severity of the disease. Under these conditions, PTX3 is a rapid marker for primary local activation of innate immunity and inflammation.
Pathogen versus apoptotic self recognition
Similar to other members of the pentraxin family PTX3 binds apoptotic cellsApoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, thereby inhibiting their recognition by DCs . Binding occurs late in the apoptotic process and enhances cytokine production by DCs. In addition, preincubation of apoptotic cells with PTX3 enhances C1q
C1Q complex
The C1q complex is potentially multivalent for attachment to the complement fixation sites of immunoglobulin.The sites are on the CH2 domain of IgG and, it is thought, on the CH4 domain of IgM....
binding and C3 deposition on the cell surface, suggesting a role for PTX3 in the complement-mediated clearance of apoptotic cells. Moreover, in the presence of dying cells, PTX3 restricts the cross presentation of antigens derived from dying cells. These results suggest that PTX3 has a dual role: protection against pathogens and control of autoimmunity.