Phosphorylation-Regulated Interaction Of Phospho-Ser/Thr-Pro Binding Motifs With Proteins Involved In Alzheimer'S Disease & Asthma
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The intrinsic bimodal conformation of the prolyl peptide bond, characterized by the cis and trans isomers, can act as a two-state molecular switch to regulate protein function and folding. Peptidylprolyl isomerase (PPIase) enzymes exist that accelerate the otherwise slow interconversion between cis and trans isomer states. One particular PPIase, Pin1, specifically targets prolyl peptide bonds immediately preceded by phosphorylated serine (pS) or threonine (pT). Such pS/pT-P motifs are abundant in the cell, but they are transiently populated depending on the relative kinase and phosphatase activities at each particular site. Two such phosphorylation-regulated proteins, which have also been linked to disease-related processes, are the subjects of this work. The cytosolic tail of the amyloid precursor protein (APP) contains a single pT-P site (phosphoT668-P669) that has been implicated in the trafficking and proteolytic processing of APP, and elevated phosphorylation of this site is observed in Alzheimer's disease brain tissues. Work presented here shows that T668 phosphorylation weakens the core binding interface between APP and the major stress-induced heat shock factor Hsp70 that targets protein substrates for degradation. This result suggests that phosphorylation of T668 could reduce targeting of APP for degradation and thereby elevate APP levels, potentially adding a novel route by which T668 phosphorylation might increase production of the APP-derived, neurotoxic amyloid beta peptide. The interleukin-1 receptor-associated kinase 1 (IRAK1) is a key player in receptormediated innate immunity signaling. The IRAK1 undefined domain (UD) has multiple pS-P motifs that are autophosphorlyated in response to receptor stimulation. The sequence proximity of two pairs of pS-P motifs in IRAK1-UD suggests that the WW and PPIase domains of Pin1, both of which can interact with pS/pT-P motifs, could simultaneously bind to two neighboring motifs (i.e., bivalently). Quantification of individual affinities between each Pin1 domain and each of four pS-P IRAK1-UD sites formed the basis for computational modeling of the complex multi-state system that represents the putative bivalent interaction. These results suggest that the prevalence of pS/pT-P motifs in close proximity of one another in biological substrates of Pin1 might provide an important competitive advantage among the multitude of Pin1 substrates in the cell.
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