The enterrococcal cytolysin synthetase has an unanticipated lipid kinase fold

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Abstract

The enterococcal cytolysin is a virulence factor consisting of two post-translationally modified peptides that synergistically kill human immune cells. Both peptides are made by CylM, a member of the LanM lanthipeptide synthetases. CylM catalyzes seven dehydrations of Ser and Thr residues and three cyclization reactions during the biosynthesis of the cytolysin large subunit. We present here the 2.2 Å resolution structure of CylM, the first structural information on a LanM. Unexpectedly, the structure reveals that the dehydratase domain of CylM resembles the catalytic core of eukaryotic lipid kinases, despite the absence of sequence homology. The kinase and phosphate elimination active sites that effect net dehydration are immediately adjacent to each other. Characterization of mutants provided insights into the mechanism of the dehydration process. The structure is also of interest because of the interactions of human homologs of lanthipeptide cyclases with kinases such as mammalian target of rapamycin (mTOR).

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Shi-Hui Dong

Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, United States

Competing interests
No competing interests declared.
Weixin Tang

Roger Adams Laboratory, Department of Chemistry, Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, Urbana, United States

Competing interests
No competing interests declared.
Tiit Lukk

Cornell High Energy Synchrotron Source, Ithaca, United States

Competing interests
No competing interests declared.
Yi Yu

Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, United Kingdom

Competing interests
No competing interests declared.
Satish K Nair

Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, United States

Competing interests
No competing interests declared.
Wilfred A van der Donk

Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, United States

For correspondence
vddonk@illinois.edu

Competing interests
Wilfred A van der Donk, Reviewing editor, eLife.

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