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

Mirosław Książek; Theodoros Goulas; Danuta Mizgalska; Arturo Rodríguez-Banqueri; Ulrich Eckhard; Florian Veillard; Irena Waligórska; Małgorzata Benedyk-Machaczka; Alicja M. Sochaj-Gregorczyk; Mariusz Madej; Ida B. Thøgersen; Jan J. Enghild; Anna Cuppari; Joan L. Arolas; Iñaki de Diego; Mar López-Pelegrín; Irene Garcia-Ferrer; Tibisay Guevara; Vincent Dive; Marie Louise Zani; Thierry Moreau; Jan Potempa; F. Xavier Gomis-Rüth

doi:10.1039/d2sc04166a

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

Mirosław Książek, Theodoros Goulas, Danuta Mizgalska, Arturo Rodríguez-Banqueri, Ulrich Eckhard, Florian Veillard, Irena Waligórska, Małgorzata Benedyk-Machaczka, Alicja M. Sochaj-Gregorczyk, Mariusz Madej, Ida B. Thøgersen, Jan J. Enghild, Anna Cuppari, Joan L. Arolas, Iñaki de Diego, Mar López-Pelegrín, Irene Garcia-Ferrer, Tibisay Guevara, Vincent Dive, Marie Louise ZaniThierry Moreau, Jan Potempa^*, F. Xavier Gomis-Rüth

^*Corresponding author af dette arbejde

Institut for Molekylærbiologi og Genetik - Proteinvidenskab

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

4 Citationer (Scopus)

Abstract

Periodontopathogenic Tannerella forsythia 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 T. forsythia, as shown in vivo. Remarkably, PotA also contributes to bacterial fitness in vivo 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 ß-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 via 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.

Originalsprog	Engelsk
Tidsskrift	Chemical Science
Vol/bind	14
Nummer	4
Sider (fra-til)	869-888
ISSN	2041-6520
DOI	https://doi.org/10.1039/d2sc04166a
Status	Udgivet - jan. 2023

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Książek, M., Goulas, T., Mizgalska, D., Rodríguez-Banqueri, A., Eckhard, U., Veillard, F., Waligórska, I., Benedyk-Machaczka, M., Sochaj-Gregorczyk, A. M., Madej, M., Thøgersen, I. B., Enghild, J. J., Cuppari, A., Arolas, J. L., de Diego, I., López-Pelegrín, M., Garcia-Ferrer, I., Guevara, T., Dive, V., ... Gomis-Rüth, F. X. (2023). A unique network of attack, defence and competence on the outer membrane of the periodontitis pathogen Tannerella forsythia. Chemical Science, 14(4), 869-888. https://doi.org/10.1039/d2sc04166a

@article{520fb9fadb784a48b3f64d7b9d269d6e,

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

abstract = "Periodontopathogenic Tannerella forsythia 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 T. forsythia, as shown in vivo. Remarkably, PotA also contributes to bacterial fitness in vivo 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 {\ss}-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 via 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.",

author = "Miros{\l}aw Ksi{\c a}{\.z}ek and Theodoros Goulas and Danuta Mizgalska and Arturo Rodr{\'i}guez-Banqueri and Ulrich Eckhard and Florian Veillard and Irena Walig{\'o}rska and Ma{\l}gorzata Benedyk-Machaczka and Sochaj-Gregorczyk, {Alicja M.} and Mariusz Madej and Th{\o}gersen, {Ida B.} and Enghild, {Jan J.} and Anna Cuppari and Arolas, {Joan L.} and {de Diego}, I{\~n}aki and Mar L{\'o}pez-Pelegr{\'i}n and Irene Garcia-Ferrer and Tibisay Guevara and Vincent Dive and Zani, {Marie Louise} and Thierry Moreau and Jan Potempa and Gomis-R{\"u}th, {F. Xavier}",

note = "Funding Information: The authors thank Laura Company, Xandra Kreplin and Joan Pous from the joint IBMB/IRB Automated Crystallography Platform and the Protein Purification Service for assistance during purification, crystallization and SEC-MALLS experiments. The authors also thank the ESRF and ALBA synchrotrons for beamtime and the beamline staff for assistance during diffraction data collection and Dr Ashu Sharma (University of Buffalo, Buffalo, NY, USA) for providing rabbit antiserum against the BspA protein of T. forsythia. This study was supported in part by grants from Polish (National Science Centre and Ministry of Science and Higher Education), US (NIH/NIDR), Spanish, Danish and Catalan public and private bodies (grant/fellowship references PID2019-107725RG-I00 and PDC2022-133344-I00 by MICIN/AEI/10.13039/501100011033, 2017SGR3, 2016/21/B/NZ1/00292, 1306/MOB/IV/2015/0, 2019/35/B/NZ1/03118, DE026280, Fundaci{\'o} “La Marat{\'o} de TV3” 201815, and Novo Nordisk Foundation grant NNF18OC0032724). The authors thank Richard M. Twyman for editing the manuscript. Publisher Copyright: {\textcopyright} 2023 The Royal Society of Chemistry.",

year = "2023",

month = jan,

doi = "10.1039/d2sc04166a",

language = "English",

volume = "14",

pages = "869--888",

journal = "Chemical Science",

issn = "2041-6520",

publisher = "Royal Society of Chemistry",

number = "4",

}

Książek, M, Goulas, T, Mizgalska, D, Rodríguez-Banqueri, A, Eckhard, U, Veillard, F, Waligórska, I, Benedyk-Machaczka, M, Sochaj-Gregorczyk, AM, Madej, M, Thøgersen, IB , Enghild, JJ, Cuppari, A, Arolas, JL, de Diego, I, López-Pelegrín, M, Garcia-Ferrer, I, Guevara, T, Dive, V, Zani, ML, Moreau, T, Potempa, J & Gomis-Rüth, FX 2023, 'A unique network of attack, defence and competence on the outer membrane of the periodontitis pathogen Tannerella forsythia', Chemical Science, bind 14, nr. 4, s. 869-888. https://doi.org/10.1039/d2sc04166a

A unique network of attack, defence and competence on the outer membrane of the periodontitis pathogen Tannerella forsythia. / Książek, Mirosław; Goulas, Theodoros; Mizgalska, Danuta et al.
I: Chemical Science, Bind 14, Nr. 4, 01.2023, s. 869-888.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

TY - JOUR

T1 - A unique network of attack, defence and competence on the outer membrane of the periodontitis pathogen Tannerella forsythia

AU - Książek, Mirosław

AU - Goulas, Theodoros

AU - Mizgalska, Danuta

AU - Rodríguez-Banqueri, Arturo

AU - Eckhard, Ulrich

AU - Veillard, Florian

AU - Waligórska, Irena

AU - Benedyk-Machaczka, Małgorzata

AU - Sochaj-Gregorczyk, Alicja M.

AU - Madej, Mariusz

AU - Thøgersen, Ida B.

AU - Enghild, Jan J.

AU - Cuppari, Anna

AU - Arolas, Joan L.

AU - de Diego, Iñaki

AU - López-Pelegrín, Mar

AU - Garcia-Ferrer, Irene

AU - Guevara, Tibisay

AU - Dive, Vincent

AU - Zani, Marie Louise

AU - Moreau, Thierry

AU - Potempa, Jan

AU - Gomis-Rüth, F. Xavier

N1 - Funding Information: The authors thank Laura Company, Xandra Kreplin and Joan Pous from the joint IBMB/IRB Automated Crystallography Platform and the Protein Purification Service for assistance during purification, crystallization and SEC-MALLS experiments. The authors also thank the ESRF and ALBA synchrotrons for beamtime and the beamline staff for assistance during diffraction data collection and Dr Ashu Sharma (University of Buffalo, Buffalo, NY, USA) for providing rabbit antiserum against the BspA protein of T. forsythia. This study was supported in part by grants from Polish (National Science Centre and Ministry of Science and Higher Education), US (NIH/NIDR), Spanish, Danish and Catalan public and private bodies (grant/fellowship references PID2019-107725RG-I00 and PDC2022-133344-I00 by MICIN/AEI/10.13039/501100011033, 2017SGR3, 2016/21/B/NZ1/00292, 1306/MOB/IV/2015/0, 2019/35/B/NZ1/03118, DE026280, Fundació “La Marató de TV3” 201815, and Novo Nordisk Foundation grant NNF18OC0032724). The authors thank Richard M. Twyman for editing the manuscript. Publisher Copyright: © 2023 The Royal Society of Chemistry.

PY - 2023/1

Y1 - 2023/1

N2 - Periodontopathogenic Tannerella forsythia 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 T. forsythia, as shown in vivo. Remarkably, PotA also contributes to bacterial fitness in vivo 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 ß-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 via 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.

AB - Periodontopathogenic Tannerella forsythia 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 T. forsythia, as shown in vivo. Remarkably, PotA also contributes to bacterial fitness in vivo 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 ß-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 via 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.

UR - http://www.scopus.com/inward/record.url?scp=85145923124&partnerID=8YFLogxK

U2 - 10.1039/d2sc04166a

DO - 10.1039/d2sc04166a

M3 - Journal article

C2 - 36755705

AN - SCOPUS:85145923124

SN - 2041-6520

VL - 14

SP - 869

EP - 888

JO - Chemical Science

JF - Chemical Science

IS - 4

ER -

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

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