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Phosphorylation versus O‑GlcNAcylation: Computational Insights into the Differential Influences of the Two Competitive Post-Translational Modifications
journal contribution
posted on 2017-10-27, 00:00 authored by Lata Rani, Sairam S. MallajosyulaPhosphorylation
and O-GlcNAcylation are rapidly cycling intracellular
protein post-translational modifications (PTMs) that can compete for
the same serine (S) and threonine (T) sites. Limited crystal structure
information is available on the direct influence of these PTMs on
the underlying protein structure, especially for O-GlcNAcylation.
NMR and CD studies show that these competitive-PTMs can have the same
or differential influence on the overall secondary structure. In Tau
derived peptide fragments, it was found that phosphorylation stabilized
PPII conformations while O-GlcNAcylation destabilized the same. In
the absence of substantial structural information, we have performed
a systematic computational study utilizing PDB analysis, QM calculations,
and MD simulations to identify key structural trends upon PTM. Our
analysis of the limited PDB data set revealed conformational shifts
from PPII to α-helical geometry upon serine phosphorylation
and in the opposite direction, from α-helical to PPII geometry
upon threonine phosphorylation. Gas phase QM calculations covering
the complete Ramachandran ϕ/ψ space using model native,
phosphorylated, and O-GlcNAcylated dipeptide systems revealed preferences
toward α-helical conformations. However, the major structural
transitions were observed in the MD simulations upon the inclusion
of solvation. The model dipeptide simulations revealed a preference
for PPII and α-helical conformations for phosphorylated serine
and threonine, while O-GlcNAcylated dipeptides exhibited a complete
shift toward extended conformations, β-sheet and PPII, disfavoring
the α-helical conformation. For the Baldwin α-helix simulations,
it was found that both phosphorylation and O-GlcNAcylation destabilized
the helix; however, the destabilization was governed by H-bonding
and electrostatic interactions in the former, while the latter was
controlled by hydrophobic collapse and steric interactions. The presence
of lysine in close proximity of phosphate leads to potentially stable
salt bridge interactions, which can influence the structure on the
basis of the relative placement of the lysine with respect to the
PTM site. Similar strong lysine–phosphate contacts were observed
in the model Tau peptides, which steers the conformations toward PPII
geometries, highlighting the direct influence of the PTM on function.
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Keywords
cycling intracellular protein post-translational modificationsα- helical conformationssalt bridge interactionsCD studies showO-GlcNAcylation destabilizedphosphorylationLimited crystal structure informationmodel dipeptide simulationsPTMgas phase QM calculationsPDBNMRMD simulationsPPIIα- helical conformationinfluenceO-GlcNAcylated dipeptide systemslysineBaldwin α- helix simulationsmodel Tau peptidesserineCompetitive Post-Translational Modifications Phosphorylationthreonineα- helical geometry
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