Differential contribution of the repeats to heparin binding of HBHA, a major adhesin of Mycobacterium tuberculosis.
<h4>Background</h4>Tuberculosis remains one of the most important causes of global mortality and morbidity, and the molecular mechanisms of the pathogenesis are still incompletely understood. Only few virulence factors of the causative agent Mycobacterium tuberculosis are known. One of t...
Guardado en:
| Autores principales: | , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Public Library of Science (PLoS)
2012
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/38999e142a404dbb8646e8d32f28d108 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:38999e142a404dbb8646e8d32f28d108 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:38999e142a404dbb8646e8d32f28d1082021-11-18T07:26:07ZDifferential contribution of the repeats to heparin binding of HBHA, a major adhesin of Mycobacterium tuberculosis.1932-620310.1371/journal.pone.0032421https://doaj.org/article/38999e142a404dbb8646e8d32f28d1082012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22403657/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Tuberculosis remains one of the most important causes of global mortality and morbidity, and the molecular mechanisms of the pathogenesis are still incompletely understood. Only few virulence factors of the causative agent Mycobacterium tuberculosis are known. One of them is the heparin-binding haemagglutinin (HBHA), an important adhesin for epithelial cells and an extrapulmonary dissemination factor. HBHA mediates mycobacterial adherence to epithelial cells via the interactions of its C-terminal, lysine rich repeat domain with sulfated glycoconjugates on the surface of epithelial cells.<h4>Methodology/principal findings</h4>Using defined heparin sulfate (HS) analogs, we determined the minimal heparin fragment length for HBHA binding and structural adaptations of the HBHA heparin-binding domain (HBD) upon binding to heparin. The NMR studies show significant shifts of all residues in the HBD upon interaction with heparin, with stronger shifts in the last repeats compared to the upstream repeats, and indicated that the HS fragments with 14 sugar units cover the entire C-terminal lysine-rich domain of HBHA. The differential implication of the repeats is determined by the relative position of prolines and lysines within each repeat, and may contribute to binding specificity. GAG binding induces a non-homogeneous structural rearrangement in the HBD, with stabilization of a nascent α-helix only in the last penta-repeats.<h4>Conclusion/significance</h4>Mycobacterial HBHA undergoes structural adaptation upon interaction with GAGs, which is likely involved in binding specificities of the adhesin, and mycobacterial pathogens may use HBD polymorphisms for host or organ specificity. Further studies will aim at decoding the complementarity between HBD repeats and HS sequence.Pierre LebrunDominique RazeBernd FritzingerJean-Michel WieruszeskiFranck BietAlexander DoseMathieu CarpentierDirk SchwarzerFabrice AllainGuy LippensCamille LochtPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 3, p e32421 (2012) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Pierre Lebrun Dominique Raze Bernd Fritzinger Jean-Michel Wieruszeski Franck Biet Alexander Dose Mathieu Carpentier Dirk Schwarzer Fabrice Allain Guy Lippens Camille Locht Differential contribution of the repeats to heparin binding of HBHA, a major adhesin of Mycobacterium tuberculosis. |
| description |
<h4>Background</h4>Tuberculosis remains one of the most important causes of global mortality and morbidity, and the molecular mechanisms of the pathogenesis are still incompletely understood. Only few virulence factors of the causative agent Mycobacterium tuberculosis are known. One of them is the heparin-binding haemagglutinin (HBHA), an important adhesin for epithelial cells and an extrapulmonary dissemination factor. HBHA mediates mycobacterial adherence to epithelial cells via the interactions of its C-terminal, lysine rich repeat domain with sulfated glycoconjugates on the surface of epithelial cells.<h4>Methodology/principal findings</h4>Using defined heparin sulfate (HS) analogs, we determined the minimal heparin fragment length for HBHA binding and structural adaptations of the HBHA heparin-binding domain (HBD) upon binding to heparin. The NMR studies show significant shifts of all residues in the HBD upon interaction with heparin, with stronger shifts in the last repeats compared to the upstream repeats, and indicated that the HS fragments with 14 sugar units cover the entire C-terminal lysine-rich domain of HBHA. The differential implication of the repeats is determined by the relative position of prolines and lysines within each repeat, and may contribute to binding specificity. GAG binding induces a non-homogeneous structural rearrangement in the HBD, with stabilization of a nascent α-helix only in the last penta-repeats.<h4>Conclusion/significance</h4>Mycobacterial HBHA undergoes structural adaptation upon interaction with GAGs, which is likely involved in binding specificities of the adhesin, and mycobacterial pathogens may use HBD polymorphisms for host or organ specificity. Further studies will aim at decoding the complementarity between HBD repeats and HS sequence. |
| format |
article |
| author |
Pierre Lebrun Dominique Raze Bernd Fritzinger Jean-Michel Wieruszeski Franck Biet Alexander Dose Mathieu Carpentier Dirk Schwarzer Fabrice Allain Guy Lippens Camille Locht |
| author_facet |
Pierre Lebrun Dominique Raze Bernd Fritzinger Jean-Michel Wieruszeski Franck Biet Alexander Dose Mathieu Carpentier Dirk Schwarzer Fabrice Allain Guy Lippens Camille Locht |
| author_sort |
Pierre Lebrun |
| title |
Differential contribution of the repeats to heparin binding of HBHA, a major adhesin of Mycobacterium tuberculosis. |
| title_short |
Differential contribution of the repeats to heparin binding of HBHA, a major adhesin of Mycobacterium tuberculosis. |
| title_full |
Differential contribution of the repeats to heparin binding of HBHA, a major adhesin of Mycobacterium tuberculosis. |
| title_fullStr |
Differential contribution of the repeats to heparin binding of HBHA, a major adhesin of Mycobacterium tuberculosis. |
| title_full_unstemmed |
Differential contribution of the repeats to heparin binding of HBHA, a major adhesin of Mycobacterium tuberculosis. |
| title_sort |
differential contribution of the repeats to heparin binding of hbha, a major adhesin of mycobacterium tuberculosis. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/38999e142a404dbb8646e8d32f28d108 |
| work_keys_str_mv |
AT pierrelebrun differentialcontributionoftherepeatstoheparinbindingofhbhaamajoradhesinofmycobacteriumtuberculosis AT dominiqueraze differentialcontributionoftherepeatstoheparinbindingofhbhaamajoradhesinofmycobacteriumtuberculosis AT berndfritzinger differentialcontributionoftherepeatstoheparinbindingofhbhaamajoradhesinofmycobacteriumtuberculosis AT jeanmichelwieruszeski differentialcontributionoftherepeatstoheparinbindingofhbhaamajoradhesinofmycobacteriumtuberculosis AT franckbiet differentialcontributionoftherepeatstoheparinbindingofhbhaamajoradhesinofmycobacteriumtuberculosis AT alexanderdose differentialcontributionoftherepeatstoheparinbindingofhbhaamajoradhesinofmycobacteriumtuberculosis AT mathieucarpentier differentialcontributionoftherepeatstoheparinbindingofhbhaamajoradhesinofmycobacteriumtuberculosis AT dirkschwarzer differentialcontributionoftherepeatstoheparinbindingofhbhaamajoradhesinofmycobacteriumtuberculosis AT fabriceallain differentialcontributionoftherepeatstoheparinbindingofhbhaamajoradhesinofmycobacteriumtuberculosis AT guylippens differentialcontributionoftherepeatstoheparinbindingofhbhaamajoradhesinofmycobacteriumtuberculosis AT camillelocht differentialcontributionoftherepeatstoheparinbindingofhbhaamajoradhesinofmycobacteriumtuberculosis |
| _version_ |
1718423466794811392 |