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Spirochete flagella hook protein self-catalyze a lysinoalanine covalent cross-link for motility
Filetype[PDF - 1.80 MB]


Details:
  • Pubmed ID:
    27670115
  • Pubmed Central ID:
    PMC5077173
  • Funding:
    R21 DE023432/DE/NIDCR NIH HHS/United States
    R01 GM064664/GM/NIGMS NIH HHS/United States
    R01 AI087946/AI/NIAID NIH HHS/United States
    P41 GM103485/GM/NIGMS NIH HHS/United States
    R01 DE023080/DE/NIDCR NIH HHS/United States
    CC999999/Intramural CDC HHS/United States
    R01 AI078958/AI/NIAID NIH HHS/United States
    R01 DE023431/DE/NIDCR NIH HHS/United States
  • Document Type:
  • Collection(s):
  • Description:
    Spirochaetes are bacteria responsible for several serious diseases, including Lyme disease (Borrelia burgdorferi), syphilis (Treponema pallidum) and leptospirosis (Leptospira interrogans), and contribute to periodontal diseases (Treponema denticola)(1). These spirochaetes employ an unusual form of flagella-based motility necessary for pathogenicity; indeed, spirochaete flagella (periplasmic flagella) reside and rotate within the periplasmic space(2-11). The universal joint or hook that links the rotary motor to the filament is composed of ∼120-130 FlgE proteins, which in spirochaetes form an unusually stable, high-molecular-weight complex(9,12-17). In other bacteria, the hook can be readily dissociated by treatments such as heat(18). In contrast, spirochaete hooks are resistant to these treatments, and several lines of evidence indicate that the high-molecular-weight complex is the consequence of covalent crosslinking(12,13,17). Here, we show that T. denticola FlgE self-catalyses an interpeptide crosslinking reaction between conserved lysine and cysteine, resulting in the formation of an unusual lysinoalanine adduct that polymerizes the hook subunits. Lysinoalanine crosslinks are not needed for flagellar assembly, but they are required for cell motility and hence infection. The self-catalytic nature of FlgE crosslinking has important implications for protein engineering, and its sensitivity to chemical inhibitors provides a new avenue for the development of antimicrobials targeting spirochaetes.