From sequence to structural analysis in protein phosphorylation motifs

Biocomputing Group, Department of Biochemical Science A Rossi Fanelli, Sapienza University of Rome, P le Aldo Moro 5, Rome, Italy.
Frontiers in Bioscience (Impact Factor: 4.25). 01/2011; 16:1261-75. DOI: 10.2741/3787
Source: PubMed

ABSTRACT Phosphorylation is the most widely studied post-translational modification occurring in cells. While mass spectrometry-based proteomics experiments are uncovering thousands of novel in vivo phosphorylation sites, the identification of kinase specificity rules still remains a relatively slow and often inefficacious task. In the last twenty years, many efforts have being devoted to the experimental and computational identification of sequence and structural motifs encoding kinase-substrate interaction key residues and the phosphorylated amino acid itself. In this review, we retrace the road to the discovery of phosphorylation sequence motifs, examine the progresses achieved in the detection of three-dimensional motifs and discuss their importance in the understanding of regulation and de-regulation of many cellular processes.

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    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.
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