Large-scale analysis of redox-sensitive conditionally disordered protein regions reveal their widespread nature and key roles in high-level eukaryotic processes

Gábor Erdos; Bálint Mészáros; Dana Reichmann; Zsuzsanna Dosztányi

The redox-regulated order-to-disorder transition in the case of Hsp33 and the disorder-to-order transition of COX17 produce the active form of the proteins, however, such transitions can also be part of more complex regulatory mechanisms. For example, the cytoplasmic tail of T cell coreceptors CD4 and CD8 associate with the N-terminus of the Src-family tyrosine kinase Lck. These interactions are critical for T cell development and activation. The interacting tail regions of both CD4 and Lck were shown to be intrinsically disordered in isolation, yet assemble to a form a zinc clasp structure [34] . Interestingly, the interaction is also regulated at the level of alternative splicing [35] . The interaction prevents the internalization and degradation of CD4 by masking the dileucine motif required for the clathrin-mediated endocytosis [34] . While there is no direct evidence for redox regulation of this complex, activation and proliferation of CD4+ T cells is associated with the intracellular increase of reactive oxygen species and release of zinc [36] . This suggests that the Lck-CD4 complex could be considered as an additional example of the redox-regulated conditional disorder.