PROSITE documentation PDOC00561

TNFR/NGFR family cysteine-rich region signature and profile

A number of proteins, some of which are known to be receptors for growth factors, have been found to contain a cysteine-rich domain of about 110 to 160 amino acids in their N-terminal part, that can be subdivided into four (or in some cases, three) modules of about 40 residues containing 6 conserved cysteines. Proteins known to belong to this family [1,2,3,4] are listed below:

• Tumor Necrosis Factor type I and type II receptors (TNFR). Both receptors bind TNF-α and TNF-β, but are only similar in the cysteine-rich region.
• Shope fibroma virus soluble TNF receptor (protein T2).
• Lymphotoxin α/β receptor.
• Low-affinity nerve growth factor receptor (LA-NGFR) (p75).
• CD40 (Bp50), the receptor for the CD40L (or TRAP) cytokine.
• CD27, the receptor for the CD27L cytokine.
• CD30, the receptor for the CD30L cytokine.
• T-cell protein 4-1BB, the receptor for the 4-1BBL putative cytokine.
• FAS antigen (or APO-1), the receptor for FASL, a protein involved in apoptosis (programmed cell death).
• T-cell antigen OX40, the receptor for the OX40L cytokine.
• Wsl-1, a receptor (for a yet undefined ligand) that mediates apoptosis.
• Vaccinia virus protein A53 (SalF19R).

It has been shown [5] that the six cysteines all involved in intrachain disulfide bonds. A schematic representation of the structure of the 40 residue module of these receptors is shown below:

                  +-------------+    +--------------+
                  |             |    |              |
                 xCxxxxxxxxxxxxxCxCxxCxxxxxxxxxCxxxxCxx
                                  |            |
                                  +------------+

'C': conserved cysteine involved in a disulfide bond.

We have developed a signature pattern for the cysteine-rich region. It is based mainly on the position of the six conserved cysteines in each of the repeats. The profile spans the complete domain.