Editing Phosphorylation (section)

==Protein phosphorylation==
{{Main|Protein phosphorylation}}

[[Protein phosphorylation]] is the most abundant [[posttranslational modification|post-translational modification]] in eukaryotes. Phosphorylation can occur on [[serine]], [[threonine]] and [[tyrosine]] side chains (in other words, on their residues) through [[Phosphodiester bond|phosphoester bond]] formation, on [[histidine]], [[lysine]] and [[arginine]] through [[Phosphoramidate|phosphoramidate bonds]], and on [[aspartic acid]] and [[glutamic acid]] through mixed [[Organic acid anhydride|anhydride linkages]]. Recent evidence confirms widespread histidine phosphorylation at both the 1 and 3 N-atoms of the [[imidazole]] ring.<ref name="ncbi.nlm.nih.gov">{{cite journal | vauthors = Fuhs SR, Hunter T | title = pHisphorylation: the emergence of histidine phosphorylation as a reversible regulatory modification | journal = Current Opinion in Cell Biology | volume = 45 | pages = 8–16 | date = April 2017 | pmid = 28129587 | pmc = 5482761 | doi = 10.1016/j.ceb.2016.12.010 }}</ref><ref name="https">{{cite journal | vauthors = Fuhs SR, Meisenhelder J, Aslanian A, Ma L, Zagorska A, Stankova M, Binnie A, Al-Obeidi F, Mauger J, Lemke G, Yates JR, Hunter T | display-authors = 6 | title = Monoclonal 1- and 3-Phosphohistidine Antibodies: New Tools to Study Histidine Phosphorylation | journal = Cell | volume = 162 | issue = 1 | pages = 198–210 | date = July 2015 | pmid = 26140597 | pmc = 4491144 | doi = 10.1016/j.cell.2015.05.046 }}</ref> Recent work demonstrates widespread human protein phosphorylation on multiple non-canonical amino acids, including motifs containing phosphorylated histidine, aspartate, glutamate, [[cysteine]], arginine and lysine in HeLa cell extracts.<ref name="ReferenceC">{{cite journal | vauthors = Hardman G, Perkins S, Brownridge PJ, Clarke CJ, Byrne DP, Campbell AE, Kalyuzhnyy A, Myall A, Eyers PA, Jones AR, Eyers CE | display-authors = 6 | title = Strong anion exchange-mediated phosphoproteomics reveals extensive human non-canonical phosphorylation | journal = The EMBO Journal | volume = 38 | issue = 21 | pages = e100847 | date = October 2019 | pmid = 31433507 | pmc = 6826212 | doi = 10.15252/embj.2018100847 | doi-access = free }}</ref> However, due to the chemical lability of these phosphorylated residues, and in marked contrast to Ser, Thr and Tyr phosphorylation, the analysis of phosphorylated histidine (and other non-canonical amino acids) using standard biochemical and mass spectrometric approaches is much more challenging<ref name="ReferenceC"/><ref>{{cite journal | vauthors = Gonzalez-Sanchez MB, Lanucara F, Hardman GE, Eyers CE | title = Gas-phase intermolecular phosphate transfer within a phosphohistidine phosphopeptide dimer | journal = International Journal of Mass Spectrometry | volume = 367 | pages = 28–34 | date = June 2014 | pmid = 25844054 | pmc = 4375673 | doi = 10.1016/j.ijms.2014.04.015 | bibcode = 2014IJMSp.367...28G }}</ref><ref name="ReferenceB">{{cite journal | vauthors = Gonzalez-Sanchez MB, Lanucara F, Helm M, Eyers CE | title = Attempting to rewrite History: challenges with the analysis of histidine-phosphorylated peptides | journal = Biochemical Society Transactions | volume = 41 | issue = 4 | pages = 1089–1095 | date = August 2013 | pmid = 23863184 | doi = 10.1042/bst20130072 }}</ref> and special procedures and separation techniques are required for their preservation alongside classical Ser, Thr and Tyr phosphorylation.<ref>{{cite bioRxiv|vauthors=Hardman G, Perkins S, Ruan Z, Kannan N, Brownridge P, Byrne DP, Eyers PA, Jones AR, Eyers CE |title=Extensive non-canonical phosphorylation in human cells revealed using strong-anion exchange-mediated phosphoproteomics|year=2017|biorxiv=10.1101/202820}}</ref>

The prominent role of protein phosphorylation in [[biochemistry]] is illustrated by the huge body of studies published on the subject (as of March 2015, the [[MEDLINE]] database returns over 240,000 articles, mostly on ''protein'' phosphorylation).