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Human Tumor necrosis factor 

Tumor necrosis factor (also called cachectin, TNF-alpha, or TNFSF2) is a cytokine originally described as a mediator of septic shock but it is currently considered a master regulator of cell death, survival, and organogenesis.

Tumor necrosis factor (TNF; also named TNFa) is a type II transmembrane protein with an intracellular amino terminus. It has signalling potential both as a 26 kd membrane-integrated protein and as a soluble cytokine released after cleavage by the protease TACE; its soluble form is a trimer of 17 kDa components. There are two TNF receptors: TNFR1, which is found on most cells in the body, and TNFR2, which is primarily expressed on cells of hematopoietic origin. TNFR1 is activated by both TNF forms, while TNFR2 primarily binds transmembrane TNF. TNF receptors are also shed and act as soluble TNF-binding proteins, competing with cell surface receptors for free ligand and thus inhibiting TNF action (Locksley et al, 2001, Hehlgans et al, 2005).

The signaling pathways mediated by the two receptors are slightly divergent. TNFR1 is considered to  mediate more systemic effects. The result of its activation can lead to cell proliferation or death depending on context.  In contrast to TNFR1, TNFR2 lacks a death domain.  Its biological role  is still not fully understood, although recent evidence suggests that it can modulate the actions of TNFR1 on immune and endothelial cells. Transmembrane TNF can function as both ligand and receptor: soluble TNF receptors can bind to the cytokine on the cell surface and generate reverse signaling (Balkwill, 2009).

figure of TNF amino acid sequence

TNF Sequence (from PDB)

Gene

The human TNF gene (TNFA) was cloned in 1985 (Lloyd et al, 1985). It maps to chromosome 6p21.3 (short arm),  close or within the MHC (Major Histocompatibility Complex) region. It spans about 3 kb and contains 4 exons. The 3′ UTR of TNF alpha contains an AU-rich element (ARE), providing a means of post-transcriptional control.

Protein

The protein is translated as a 233 amino acid (26kD) type II transmembrane protein, which is further cleaved by the protease TACE (ADAM 17). Both forms exist as trimers. The 17 kd TNF protomers (185-amino acid-long) are composed of two antiparallel β-pleated sheets with antiparallel β-strands, forming a ‘jelly roll’ β-structure, typical for the TNF family.

Here are two renderings of TNF from the PDB site. However, for the 3D effects you may want to visit the Jmol view.

PDB rendering of TNF

PDB rendering of TNF

molecular view of TNF

Another rendering of TNF

Protein Databank Reference (PDB): 1TNF 

Uniprot entry: P01375 

NCBI RefSeq : NP000585.2

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