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Nat Chem Biol. 2019 Aug 12. doi: 10.1038/s41589-019-0341-3. [Epub ahead of print]

Structure and chemistry of lysinoalanine crosslinking in the spirochaete flagella hook.

Author information

1
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, USA.
2
Department of Biochemistry, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV, USA.
3
Department of Microbiology, Immunology, and Cell Biology, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV, USA.
4
Proteomics Facility, Institute of Biotechnology, Cornell University, Ithaca, NY, USA.
5
Philips Institute for Oral Health Research, Virginia Commonwealth University School of Dentistry, Richmond, VA, USA.
6
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, USA. bc69@cornell.edu.

Abstract

The flagellar hook protein FlgE from spirochaete bacteria self-catalyzes the formation of an unusual inter-subunit lysinoalanine (Lal) crosslink that is critical for cell motility. Unlike other known examples of Lal biosynthesis, conserved cysteine and lysine residues in FlgE spontaneously react to form Lal without the involvement of additional enzymes. Oligomerization of FlgE via its D0 and Dc domains drives assembly of the crosslinking site at the D1-D2 domain interface. Structures of the FlgED2 domain, dehydroalanine (DHA) intermediate and Lal crosslinked FlgE subunits reveal successive snapshots of the reaction. Cys178 flips from a buried configuration to release hydrogen sulfide (H2S/HS-) and produce DHA. Interface residues provide hydrogen bonds to anchor the active site, facilitate β-elimination of Cys178 and polarize the peptide backbone to activate DHA for reaction with Lys165. Cysteine-reactive molecules accelerate DHA formation, whereas nucleophiles can intercept the DHA intermediate, thereby indicating a potential for Lal crosslink inhibitors to combat spirochaetal diseases.

PMID:
31406373
DOI:
10.1038/s41589-019-0341-3

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