Leptospira interrogans Endostatin-Like Outer Membrane Proteins Bind Host Fibronectin, Laminin and Regulators of Complement

Stevenson, Brian; Choy, Henry A.; Pinne, Marija; Rotondi, Matthew L.; Miller, Michael C.; DeMoll, Edward; Kraiczy, Peter; Cooley, Anne; Creamer, T.; Suchard, Marc A.; Brissette, Catherine A.; Verma, Ashutosh; Haake, David A.

doi:10.1371/journal.pone.0001188

Cited by 209 publications

(233 citation statements)

References 71 publications

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“…The high affinity of Lsa23 to laminin (K D = 25.08 ± 4.1 nM), a value of the same order of magnitude as a described Lsa66 adhesin. 15 The K D values of Lsa26 and Lsa36 are similar to the ones described for LenB, 46 TlyC, 47 OmpL37, 48 Lsa20, 16 Lsa33, and Lsa25 17 and Lsa30 18 with the same ligand. PLG acquisition and PLA generation has been reported for several pathogens, including the spirochetes Borrelia spp.…”

Section: Discussionsupporting

confidence: 75%

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Characterization of Three Novel Adhesins of Leptospira interrogans

Siqueira¹,

Atzingen²,

Alves³

et al. 2013

The American Journal of Tropical Medicine and Hygiene

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Abstract. We report cloning, expression, purification, and characterization of three predicted leptospiral membrane proteins (LIC11360, LIC11009, and LIC11975). In silico analysis and proteinase K accessibility data suggest that these proteins might be surface exposed. We show that proteins encoded by LIC11360, LIC11009 and LIC11975 genes interact with laminin in a dose-dependent and saturable manner. The proteins are referred to as leptospiral surface adhesions 23, 26, and 36 (Lsa23, Lsa26, and Lsa36), respectively. These proteins also bind plasminogen and generate active plasmin. Attachment of Lsa23 and Lsa36 to fibronectin occurs through the involvement of the 30-kDa and 70-kDa heparin-binding domains of the ligand. Dose-dependent, specific-binding of Lsa23 to the complement regulator C4BP and to a lesser extent, to factor H, suggests that this protein may interfere with the complement cascade pathways. Leptospira spp. may use these interactions as possible mechanisms during the establishment of infection.

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Section: Discussionsupporting

confidence: 75%

“…62 Leptospiral binding proteins to C4BP, factor H, and factor H-like have been identified in Leptospira. 17,18,46,[63][64][65][66] We report that Lsa23 is a novel C4BP and factor H binding protein of Leptospira, although with the ligand affinity for factor H binding protein seems to be low.…”

Section: Discussionmentioning

confidence: 88%

Characterization of Three Novel Adhesins of Leptospira interrogans

Siqueira¹,

Atzingen²,

Alves³

et al. 2013

The American Journal of Tropical Medicine and Hygiene

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“…Several plasminogen binding bacterial proteins interact through their lysine residues (8,19,49). LenA has several lysine residues, mostly spread on its amino-terminal two-thirds (42). The addition of a synthetic lysine analog -aminocaproic FIG.…”

Section: Leptospira Interrogans Binds Human Plasminogenmentioning

confidence: 99%

Leptospiral Endostatin-Like Protein A Is a Bacterial Cell Surface Receptor for Human Plasminogen

et al. 2010

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The spirochete Leptospira interrogans is a highly invasive pathogen of worldwide public health importance. Studies from our laboratories and another have demonstrated that L. interrogans can acquire host plasminogen on its surface. Exogenous plasminogen activators can then convert bound plasminogen into the functionally active protease plasmin. In this study, we extend upon those observations and report that leptospiral endostatin-like protein A (LenA) binds human plasminogen in a dose-dependent manner. LenA-plasminogen interactions were significantly inhibited by the lysine analog -aminocaproic acid, suggesting that the lysine-binding sites on the amino-terminal kringle portion of the plasminogen molecule play a role in the binding. Previous studies have shown that LenA also binds complement regulator factor H and the extracellular matrix component laminin. Plasminogen competed with both factor H and laminin for binding to LenA, which suggests overlapping ligand-binding sites on the bacterial receptor. Finally, LenA-bound plasminogen could be converted to plasmin, which in turn degraded fibrinogen, suggesting that acquisition of host-derived plasmin by LenA may aid bacterial dissemination throughout host tissues.

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“…Several pathogenic bacteria interact with ECM components (11,12,(25)(26)(27)(28)(29)(30)(31)(32) or other host molecules such as plasminogen (13,(33)(34)(35) to facilitate host colonization. Accordingly, leptospires employ surface-exposed proteins to bind to a wide range of host ligands, including laminin, collagen, cellular and plasma fibronectin, elastin, proteoglycans, fibrinogen, and plasminogen (13,30,31,36,37).…”

Section: Discussionmentioning

confidence: 99%

Calcium Binding to Leptospira Outer Membrane Antigen LipL32 Is Not Necessary for Its Interaction with Plasma Fibronectin, Collagen Type IV, and Plasminogen

Hauk

Barbosa

et al. 2012

Journal of Biological Chemistry

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LipL32 is the most abundant outer membrane protein from pathogenic Leptospira and has been shown to bind extracellular matrix (ECM) proteins as well as Ca 2؉ . Recent crystal structures have been obtained for the protein in the apo-and Ca 2؉ -bound forms. In this work, we produced three LipL32 mutants (D163-168A, Q67A, and S247A) and evaluated their ability to interact with Ca 2؉ and with ECM glycoproteins and human plasminogen. The D163-168A mutant modifies aspartate residues involved in Ca 2؉ binding, whereas the other two modify residues in a cavity on the other side of the protein structure. Loss of calcium binding in the D163-D168A mutant was confirmed using intrinsic tryptophan fluorescence, circular dichroism, and thermal denaturation whereas the Q67A and S247A mutants presented the same Ca 2؉ affinity as the wild-type protein. We then evaluated if Ca 2؉ binding to LipL32 would be crucial for its interaction with collagen type IV and plasma proteins fibronectin and plasminogen. Surprisingly, the wild-type protein and all three mutants, including the D163-168A variant, bound to these ECM proteins with very similar affinities, both in the presence and absence of Ca 2؉ ions. In conclusion, calcium binding to LipL32 may be important to stabilize the protein, but is not necessary to mediate interaction with host extracellular matrix proteins.

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Leptospira interrogans Endostatin-Like Outer Membrane Proteins Bind Host Fibronectin, Laminin and Regulators of Complement

Cited by 209 publications

References 71 publications

Characterization of Three Novel Adhesins of Leptospira interrogans

Characterization of Three Novel Adhesins of Leptospira interrogans

Leptospiral Endostatin-Like Protein A Is a Bacterial Cell Surface Receptor for Human Plasminogen

Calcium Binding to Leptospira Outer Membrane Antigen LipL32 Is Not Necessary for Its Interaction with Plasma Fibronectin, Collagen Type IV, and Plasminogen

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