title: Lysine pyrrolation is a naturally-occurring covalent modification involved in the production of DNA mimic proteins.
abstract: Covalent modification of proteins exerts significant effects on their chemical properties and has important functional and regulatory consequences. We now report the identification and verification of an electrically-active form of modified proteins recognized by a group of small molecules commonly used to interact with DNA. This previously unreported property of proteins was initially discovered when the γ-ketoaldehydes were identified as a source of the proteins stained by the DNA intercalators. Using 1,4-butanedial, the simplest γ-ketoaldehyde, we characterized the structural and chemical criteria governing the recognition of the modified proteins by the DNA intercalators and identified N(ε)-pyrrolelysine as a key adduct. Unexpectedly, the pyrrolation conferred an electronegativity and electronic properties on the proteins that potentially constitute an electrical mimic to the DNA. In addition, we found that the pyrrolated proteins indeed triggered an autoimmune response and that the production of specific antibodies against the pyrrolated proteins was accelerated in human systemic lupus erythematosus. These findings and the apparent high abundance of N(ε)-pyrrolelysine in vivo suggest that protein pyrrolation could be an endogenous source of DNA mimic proteins, providing a possible link connecting protein turnover and immune disorders.
authors.affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Miyashita
authors.affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Chikazawa
authors.affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan.
authors.forename: Natsuki
authors.initials: N
authors.lastname: Otaki
authors.affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Hioki
authors.affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Shimozu
authors.affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan.
authors.forename: Fumie
authors.initials: F
authors.lastname: Nakashima
authors.affiliation: 1] Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan [2] PRESTO, Japan Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shibata
authors.affiliation: National Institute of Advanced Industrial Science and Technology (AIST), Ikeda, Osaka 563-8577, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Hagihara
authors.affiliation: Department of Nephrology, Graduate School of Medical Sciences, Nagoya University, Nagoya 466-8550, Japan.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Maruyama
authors.affiliation: School of Materials Science, Japan Advanced Institute of Science and Technology, Ishikawa 923-1292, Japan.
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Matsumi
authors.affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Uchida
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D052160:Benzothiazoles; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D003959:Diamines; D004996:Ethidium / Q000737:chemistry / Q000378:metabolism; D005260:Female; D005456:Fluorescent Dyes / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism; D008239:Lysine / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D008807:Mice, Inbred BALB C; D019463:Mice, Inbred MRL lpr; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009930:Organic Chemicals / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism; D011804:Quinolines; D013050:Spectrometry, Fluorescence
chemical_list: D052160:Benzothiazoles; D003959:Diamines; D005456:Fluorescent Dyes; D009930:Organic Chemicals; D011506:Proteins; D011758:Pyrroles; D011804:Quinolines; C098022:SYBR Green I; D004247:DNA; D004996:Ethidium; D008239:Lysine