Evolution of immunity: no development without risk.

Signal transduction by cell surface receptors in the context of heterogeneous and variable cellular environments plays a pivotal role in regulating many biological processes, including development, activation, and homeostasis of the immune system. In some receptors, extracellular ligand-binding and intracellular signaling domains are located on the same protein chain (single-chain receptors), while in the so-called multichain immune recognition receptors (MIRRs), recognition and signaling functions are separated between different protein chains. Why did nature separate recognition and signaling functions for MIRRs, thereby increasing the risk of malfunction and potential attack by pathogens? The risk is real: in order to escape the immune response, viruses are able to disrupt functional coupling between recognition and signaling aspects of MIRR machinery. Intrinsic disorder of intracellular signal-generating regions of MIRRs adds further intrigue to the story. Why did nature select protein disorder for MIRRs to translate recognition of distinct antigens into appropriate activation signals that would induce specific functional outcomes? Here, I suggest that nature takes the risks associated with intrareceptor separation of functions as well as with the chaos and indeterminacy of protein disorder in exchange for providing diversity and variability of signal transduction. Not only does this phenomenon serve as the molecular basis for the development and evolution of the immune and other complex biological systems, but it fits closely to Darwinian evolutionary biology.