Intrinsic disorder associated with 14-3-3 proteins and their partners
Sluchanko, Nikolai N.; Bustos, Diego Martin; Intrinsic disorder associated with 14-3-3 proteins and their partners; Elsevier; Progress In Molecular Biology And Translational Science; 166; 1-2019; 19-61
Sluchanko, Nikolai N.
Bustos, Diego Martin
Protein-protein interactions (PPIs) mediate a variety of cellular processes and form complex networks, where connectivity is achieved owing to the “hub” proteins whose interaction with multiple protein partners is facilitated by the intrinsically disordered protein regions (IDPRs) and posttranslational modifications (PTMs). Universal regulatory proteins of the eukaryotic 14-3-3 family nicely exemplify these concepts and are the focus of this chapter. The extremely wide interactome of 14-3-3 proteins is characterized by high levels of intrinsic disorder (ID) enabling protein phosphorylation and consequent specific binding to the well-structured 14-3-3 dimers, one of the first phosphoserine/phosphothreonine binding modules discovered. However, high ID enrichment also challenges structural studies, thereby limiting the progress in the development of small molecule modulators of the key 14-3-3 PPIs of increased medical importance. Besides the well-known structural flexibility of their variable C-terminal tails, recent studies revealed the strong and conserved ID propensity hidden in the N-terminal segment of 14-3-3 proteins (~ 40 residues), normally forming the α-helical dimerization region, that may have a potential role for the dimer/monomer dynamics and recently reported moonlighting chaperone-like activity of these proteins. We review the role of ID in the 14-3-3 structure, their interactome, and also in selected 14-3-3 complexes. In addition, we discuss approaches that, in the future, may help minimize the disproportion between the large amount of known 14-3-3 partners and the small number of 14-3-3 complexes characterized with atomic precision, to unleash the whole potential of 14-3-3 PPIs as drug targets.
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