Structure and Specificity of the Bacterial Cysteine Methyltransferase Effector NleE Suggests a Novel Substrate in Human DNA Repair Pathway

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Pathogens often manipulate host functions by posttranslational modifications such as ubiquitination and methylation. The NF-κB pathway is most critical for immune defense against infection, thereby frequently targeted by bacterial virulence factors. NleE, a virulence effector from EPEC, is a SAM-dependent methyltransferase that modifies a zinc-finger cysteine in TAB2/3 in the NF-κB pathway. NleE is not homologous to any known methyltransferases. We present the crystal structure of SAM-bound NleE that shows a novel methyltransferase fold with a unique SAM-binding mode. Computational docking and molecular dynamics simulation illustrate a structural and chemical mechanism underlying NleE recognition of the NZF and catalyzing site-specific cysteine methylation. Subsequent substrate specificity analyses identify an N-terminal region in TAB3 required for efficient NleE recognition as well as another NZF protein ZRANB3 being a new substrate of NleE. NleE-catalyzed cysteine methylation also disrupts the ubiquitin chain-binding of ZRANB3-NZF domain, providing new insights into ZRANB3-NZF functioning in DNA damage repair. These results reinforce the idea of harnessing bacterial effectors as a tool for dissecting eukaryotic functions.

Vyšlo v časopise: Structure and Specificity of the Bacterial Cysteine Methyltransferase Effector NleE Suggests a Novel Substrate in Human DNA Repair Pathway. PLoS Pathog 10(11): e32767. doi:10.1371/journal.ppat.1004522
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004522

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