title: Influence of nonenzymatic posttranslational modifications on constitution, oligomerization and receptor binding of S100A12.
abstract: This study examined the effect of methylglyoxal (MGO)-derived nonenzymatic posttranslational modifications (nePTMs) on the binding affinity of S100A12 to its natural receptor for advanced glycation end-products (RAGE). Binding of MGO-modified S100A12 to RAGE decreased significantly with increasing MGO concentration and incubation time. Ca(2+)-induced S100A12 hexamerization was impaired only at higher MGO concentrations indicating that the loss of affinity is not predominantly caused by disturbance of ligand oligomerization. nePTM mapping showed carboxyethylation of lysine (CEL) and the N-terminus without preferential modification sites. Besides, hydroimidazolone, hemiaminals, argpyrimidine, and tetrahydropyrimidine rapidly formed at R21. Even at the highest modification rate, hexamerization of synthesized CEL-S100A12 was unaffected and RAGE-binding only slightly impaired. Thus, nePTMs at R21 seem to be the major cause of MGO-induced impairment of S100A12 oligomerization and RAGE binding.
authors.affiliation: Department of Chemistry and Pharmacy, Food Chemistry Division, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Augner
authors.affiliation: Department of Chemistry and Pharmacy, Medicinal Chemistry Division, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Jutta
authors.initials: J
authors.lastname: Eichler
authors.affiliation: Department of Chemistry and Pharmacy, Food Chemistry Division, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Utz
authors.affiliation: Department of Chemistry and Pharmacy, Food Chemistry Division, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Pischetsrieder
mesh_terms: D000586:Amination; D000818:Animals; D001120:Arginine / Q000737:chemistry; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D007700:Kinetics; D008239:Lysine / Q000737:chemistry; D051379:Mice; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D011743:Pyrimidines / Q000737:chemistry; D011765:Pyruvaldehyde / Q000737:chemistry; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry; D009418:S100 Proteins / Q000737:chemistry*; D000067616:S100A12 Protein; D012996:Solutions
chemical_list: D007093:Imidazoles; D011743:Pyrimidines; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; D009418:S100 Proteins; D000067616:S100A12 Protein; C090441:S100A12 protein, human; D012996:Solutions; C117197:imidazolone; D011765:Pyruvaldehyde; D001120:Arginine; D008239:Lysine