Abstract
Hub proteins interact with a host of client proteins and regulate multiple cellular functions. Dynamic hubs have a single binding interface for one client at a time resulting in competition among clients with the highest affinity. Dynamic dimeric hubs with two identical sites bind either two different client proteins or two chains of the same client to form homogenous complexes and could also form heterogeneous mixtures of interconverting complexes. Here, we review the interactions of the dimeric hubs 14-3-3 and LC8. 14-3-3 is a phosphoserine/threonine binding protein involved in structuring client proteins and regulating their phosphorylation. LC8 is involved in promoting the dimerization of client peptides and the rigidification of their disordered regions. Both 14-3-3 and LC8 are essential genes, with 14-3-3 playing a crucial role in apoptosis and cell cycle regulation, while LC8 is critical for the assembly of proteins involved in transport, DNA repair, and transcription. Interestingly, both protein dimers can dissociate by phosphorylation, which results in their interactome-wide changes. Their interactions are also regulated by the phosphorylation of their clients. Both form heterogeneous complexes with various functions including phase separation, signaling, and viral hijacking where they restrict the conformational heterogeneity of their dimeric clients that bind nucleic acids. This comparative analysis highlights the importance of dynamic protein-protein interactions in the diversity of functions of 14-3-3 and LC8 and how small differences in structures of interfaces explain why 14-3-3 is primarily involved in the regulation of phosphorylation states while LC8 is primarily involved in the regulation of assembly of large dynamic complexes.