Differential occurrence of protein intrinsic disorder in the cytoplasmic signaling domains of cell receptors.

In human membrane proteins, intrinsically disordered regions, the regions that lack a well-defined three-dimensional structure under physiological conditions, preferentially occur in the cytoplasmic tails. Many of these proteins represent cell receptors that function by recognizing their cognate ligand outside the cell and translating this binding information into an intracellular activation signal. Based on location of recognition and signaling (effector) domains, functionally diverse and unrelated cell receptors can be classified into two main families: those in which binding and signaling domains are located on the same protein chain, the so-called single-chain receptors (SRs), and those in which these domains are intriguingly located on separate subunits, the so-called multichain receptors (MRs). Recognition domains of both SRs and MRs are known to be well ordered. In contrast, while cytoplasmic signaling domains of SRs are well-structured as well, those of MRs are intrinsically disordered. Despite important role of receptor signaling in health and disease, extensive comparative structural analysis of receptor signaling domains has not been carried out as of yet. In this study, using a variety of prediction algorithms, we show that protein disorder is a characteristic and distinctive feature of receptors with recognition and signaling functions distributed between separate protein chains. We also reveal that disorder distribution patterns are rather similar within SR subclasses suggesting potential functional explanations. Why did nature select protein disorder to provide intracellular signaling for MRs? Is there any correlation between disorder profiles of signaling domains and receptor function? These and other questions are addressed in this article.