Phosphorylation versus O-GlcNAcylation: Computational Insights into the Differential Influences of the Two Competitive Post-Translational Modifications

The Journal of Physical Chemistry. B
Lata Rani, Sairam S Mallajosyula

Abstract

Phosphorylation 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 conformation...Continue Reading

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Citations

Oct 11, 2019·Journal of Biomolecular NMR·Ruth Hendus-AltenburgerBirthe B Kragelund
Jul 19, 2019·Journal of Biomolecular NMR·Anne C ConibearHanspeter Kaehlig
Jun 12, 2018·Cellular Immunology·Tristan de JesusParameswaran Ramakrishnan
Aug 3, 2021·Chemical Society Reviews·Abhijit SahaAlberto Fernández-Tejada
Nov 24, 2018·Journal of Chemical Theory and Computation·Jiří VymětalJiří Vondrášek
Dec 7, 2021·The Journal of Physical Chemistry. B·Lata Rani, Sairam S Mallajosyula

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