Abstract
Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic inflammatory cytokine that exerts potent cytotoxic effects on solid tumor cells, while not affecting their normal counterparts. It is also known that TNF-alpha exerts many of its biological functions via interaction with specific receptors. To understand the potential roles of intrinsic disorder in the functioning of this important cytokine, we explored the peculiarities of intrinsic disorder distribution in human TNF-alpha and its homologs from various species, ranging from zebrafish to chimpanzee. We also studied the peculiarities of intrinsic disorder distribution in human TNF-alpha receptors, TNFR1 and TNFR2. Analysis revealed that cytoplasmic domains of TNF-alpha and its receptors are expected to be highly disordered. Furthermore, although the sequence identities of analyzed TNF-alpha homologs range from 99.57% (between human and chimpanzee proteins) to 22.33% (between frog and fish proteins), their intrinsic disorder profiles are characterized by a remarkable similarity. These observations indicate that the peculiarities of distribution of the intrinsic disorder propensity within the amino acid sequences are evolutionary conserved, and therefore could be of functional importance for this family of proteins. We also show that disordered and flexible regions of human TNF-alpha and its TNFR1 and TNFR2 receptors are crucial for some of their biological activities.