Short name: TNF_beta
Overlapping homologous superfamilies
- Tumour necrosis factor (IPR006053)
- Lymphotoxin-alpha (IPR002960)
Cytokines can be grouped into a family on the basis of sequence, functional and structural similarities [PMID: 8095800, PMID: 1377364, PMID: 15335677]. Tumor necrosis factor (TNF) (also known as TNF-alpha or cachectin) is a monocyte-derived cytotoxin that has been implicated in tumour regression, septic shock and cachexia [PMID: 2989794, PMID: 3349526]. The protein is synthesised as a prohormone with an unusually long and atypical signal sequence, which is absent from the mature secreted cytokine [PMID: 2268312]. A short hydrophobic stretch of amino acids serves to anchor the prohormone in lipid bilayers [PMID: 2777790]. Both the mature protein and a partially-processed form of the hormone are secreted after cleavage of the propeptide [PMID: 2777790].
There are a number of different families of TNF, but all these cytokines seem to form homotrimeric (or heterotrimeric in the case of LT-alpha/beta) complexes that are recognised by their specific receptors.
Lymphotoxin-alpha (LT-alpha or TNF-beta) and lymphotoxin-beta (LT-beta) are related cytokines produced by lymphocytes. The proteins are cytotoxic for a wide range of tumour cells in vitro and in vivo.
The structure of TNF-beta has been determined to 1.9 A using X-ray crystallography and phase determination via molecular replacement using TNF-alpha. Like TNF-alpha, lymphotoxin folds to form a 'jellyroll' beta- sheet sandwich. Three-fold related LT subunits form a trimer primarily stabilised by hydrophobic interactions. A cluster of 6 basic residues around the 3-fold axis is thought to account for the acid lability of the trimer. Although the structural cores of TNF-alpha and LT are similar, insertions and deletions relative to TNF-alpha occur in loops at the 'top' of the LT trimer, significantly altering the local structure. The sites of two mutations (Asp-50 and Tyr-108) that abolish the cytotoxicity of LT are contained within poorly-ordered loops that flank the cleft between neighbouring subunits at the base of the molecule, suggesting that the receptor recognises an intersubunit binding site [PMID: 1733919].
- PR01236 (TNFBETA)