Abstract
PIN1 is a phosphorylation-directed member of the peptidyl-prolyl cis/trans isomerase (PPIase) family that facilitates conformational changes in phosphorylated targets such as c-MYC (MYC). Following signaling events that mediate phosphorylation of MYC at Serine 62, PIN1 establishes structurally distinct pools of MYC through its trans-cis and cis-trans isomerization activity at Proline 63. Through these isomerization steps, PIN1 functionally regulates MYC’s stability, the molecular timing of its DNA binding and transcriptional activity, and its subnuclear localization. Recently, our group showed that Serine 62 phosphorylated MYC can associate with the inner basket of the nuclear pore (NP) in a PIN1-dependent manner. The poised euchromatin at the NP basket enables rapid cellular response to environmental signals and cell stress, and PIN1-mediated trafficking of MYC calibrates this response. In this perspective, we describe the molecular aspects of PIN1 target recognition and PIN1’s function in the context of its temporal and spatial regulation of MYC.
Highlights
Proline isomerization of cellular proteins provides post-translational control of target protein structure, and function, within the cell
PIN1 affects a variety of target transcription factors in such cascades, but we focus on work describing PIN1’s temporal and spatial control of the bHLH-LZ transcription factor c-MYC, which PIN1 functionally regulates in both physiologic and pathologic responses
Using proximity ligation assay (PLA) with confocal microscopy and super-resolution stochastic optical reconstruction microscopy (STORM), we showed that pS62MYC associated with the interior basket proteins of the nuclear pore (NP) complex (NPC) (Su et al, 2018)
Summary
Following signaling events that mediate phosphorylation of MYC at Serine 62, PIN1 establishes structurally distinct pools of MYC through its trans-cis and cis-trans isomerization activity at Proline 63 Through these isomerization steps, PIN1 functionally regulates MYC’s stability, the molecular timing of its DNA binding and transcriptional activity, and its subnuclear localization. The poised euchromatin at the NP basket enables rapid cellular response to environmental signals and cell stress, and PIN1mediated trafficking of MYC calibrates this response. In this perspective, we describe the molecular aspects of PIN1 target recognition and PIN1’s function in the context of its temporal and spatial regulation of MYC
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