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Review
. 2014 Aug 7:5:270.
doi: 10.3389/fgene.2014.00270. eCollection 2014.

Physicochemical mechanisms of protein regulation by phosphorylation

Hafumi Nishi  1 , Alexey Shaytan  2 , Anna R Panchenko  2
Affiliations
Review

Physicochemical mechanisms of protein regulation by phosphorylation

Hafumi Nishi et al. Front Genet. .

Abstract

Phosphorylation offers a dynamic way to regulate protein activity and subcellular localization, which is achieved through its reversibility and fast kinetics. Adding or removing a dianionic phosphate group somewhere on a protein often changes the protein's structural properties, its stability and dynamics. Moreover, the majority of signaling pathways involve an extensive set of protein-protein interactions, and phosphorylation can be used to regulate and modulate protein-protein binding. Losses of phosphorylation sites, as a result of disease mutations, might disrupt protein binding and deregulate signal transduction. In this paper we focus on the effects of phosphorylation on protein stability, dynamics, and binding. We describe several physico-chemical mechanisms of protein regulation through phosphorylation and pay particular attention to phosphorylation in protein complexes and phosphorylation in the context of disorder-order and order-disorder transitions. Finally we assess the role of multiple phosphorylation sites in a protein molecule, their possible cooperativity and function.

Keywords: allosteric regulation; multisite phosphorylation; protein disorder; protein phosphorylation; protein–protein interactions.

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Figures

FIGURE 1
FIGURE 1
Phosphorylation and disorder–order transition. CENP-T-Spc24/Spc25 complex (PDBID: 3VZA). CENP-T, Spc24, and Spc25 are colored in pink, green, and blue, respectively. CENP-T has an N-terminal disordered region (shown in the dashed line) which folds when it binds to Spc24/Spc25. Phosphomimetic Thr72Asp mutant forms a salt bridge with Arg74 (shown in stick models), which enhances an interaction between CENP-T and Spc24/Spc25.
FIGURE 2
FIGURE 2
Regulation of multisite phosphorylation. (A) A phosphorylated model of Rb constructed based on 4ELJ and 4ELL PDB structures [as described in the previous paper (Rubin, 2013)]. Thr373 phosphorylation (shown in sphere model) induces the association between RbN (gray) and Pocket (blue) whereas Ser608 phosphorylation (shown in sphere model) allows an intra-domain loop (cyan) to directly bind to the cleft. (B) A model of the cyclin–Cdk–Cks1 complex with the relevant substrate peptide constructed based on 1BUH, 2CCI, and 4LPA PDB structures [as described in the previous paper (Koivomagi et al., 2013)]. Cyclin, Cdk, Cks1, and the peptide are colored in red, orange, green, and blue, respectively. Phosphorylated Thr at the priming phosphorylation site and Ser at the secondary phosphorylation sites are shown in sphere models. Structural superposition and model building was performed with Pymol.
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