A unique network of attack, defence and competence on the outer membrane of the periodontitis pathogen Tannerella forsythia

• Published in: Chemical science (Cambridge) Vol. 14; no. 4; pp. 869 - 888
• Main Authors: Książek, Mirosław, Goulas, Theodoros, Mizgalska, Danuta, Rodríguez-Banqueri, Arturo, Eckhard, Ulrich, Veillard, Florian, Waligórska, Irena, Benedyk-Machaczka, Małgorzata, Sochaj-Gregorczyk, Alicja M, Madej, Mariusz, Thøgersen, Ida B, Enghild, Jan J, Cuppari, Anna, Arolas, Joan L, de Diego, Iñaki, López-Pelegrín, Mar, Garcia-Ferrer, Irene, Guevara, Tibisay, Dive, Vincent, Zani, Marie-Louise, Moreau, Thierry, Potempa, Jan, Gomis-Rüth, F Xavier
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 25-01-2023; The Royal Society of Chemistry
• Subjects: Chemistry; Homology; Life Sciences; Lipoproteins; Macrophages; Matrix metalloproteinases; Membranes; Peptidases; Virulence; Tannerella forsythia
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/d2sc04166a

Periodontopathogenic
uniquely secretes six peptidases of disparate catalytic classes and families that operate as virulence factors during infection of the gums, the KLIKK-peptidases. Their coding genes are immediately downstream of novel ORFs encoding the 98-132 residue potempins (Pot) A, B1, B2, C, D and E. These are outer-membrane-anchored lipoproteins that specifically and potently inhibit the respective downstream peptidase through stable complexes that protect the outer membrane of
, as shown
. Remarkably, PotA also contributes to bacterial fitness
and specifically inhibits matrix metallopeptidase (MMP) 12, a major defence component of oral macrophages, thus featuring a novel and highly-specific physiological MMP inhibitor. Information from 11 structures and high-confidence homology models showed that the potempins are distinct β-barrels with either a five-stranded OB-fold (PotA, PotC and PotD) or an eight-stranded up-and-down fold (PotE, PotB1 and PotB2), which are novel for peptidase inhibitors. Particular loops insert like wedges into the active-site cleft of the genetically-linked peptidases to specifically block them either
a new "bilobal" or the classic "standard" mechanism of inhibition. These results discover a unique, tightly-regulated proteolytic armamentarium for virulence and competence, the KLIKK-peptidase/potempin system.