High Affinity Streptococcal Binding to Human Fibronectin Requires Specific Recognition of Sequential F1 Modules

Schwarz‐Linek, Ulrich; Pilka, E.S.; Pickford, Andrew R.; Kim, Jung Hwa; Höök, Magnus; Campbell, Iain D.; Potts, Jennifer R.

doi:10.1074/jbc.m405083200

Cited by 62 publications

(80 citation statements)

References 46 publications

(64 reference statements)

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“…One possible explanation is the formation of a "fuzzy complex," or a dynamic ensemble of conformational states, upon binding NTD. This has been previously observed for other intrinsically disordered proteins, including the NTD-binding SfbI of S. pyogenes (39,40). Regardless of the origin of the peak disappearance, the NMR experiments indicate that NTD interacts specifically with the disordered region of LigBCen2 in the intact construct.…”

Section: Identification Of the Binding Sites Of Ntd On Ligbcen2-insupporting

confidence: 76%

“…The ␤-strand-rich conformation formed by LigBCen2NR after binding NTD observed via far UV CD spectroscopy suggests that the binding of LigBCen2NR to NTD might be also mediated by a ␤-zipper interaction. However, the entropy-driven interaction of LigBCen2NR and NTD is distinct from the enthalpy-driven binding of other bacterial proteins known to bind NTD via the ␤-zipper interaction (Table 1) (23,39,46). In addition, we are unable to identify substantial sequence similarity between LigBCen2NR and BBK32 or other Fn-binding proteins, so additional study is needed to further characterize the binding between LigBCen2NR and NTD.…”

Section: Discussionmentioning

confidence: 89%

“…Similarly, upon binding to NTD, LigBCen2NR folds into a ␤-strand-rich structure, much like the D123 domain of FnbPA or the N-terminal of BBK32 (21). High resolution structures of the complex between the B3 region of FnbB and the first and the second type I module of Fn (17,18) and the complex between the first or the fifth Fn binding region of FnbpA and the second to the fifth type I module of Fn (23,39,46) all indicate that a two ␤-strand complex, called a ␤-zipper, mediates those interactions. The binding of Sfb and BBK32 to NTD are also accomplished through the ␤-zipper interaction (23, 39, 46).…”

Section: Discussionmentioning

confidence: 99%

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Fibronectin Binds to and Induces Conformational Change in a Disordered Region of Leptospiral Immunoglobulin-like Protein B

Lin¹,

Greenwood

Nicholson

et al. 2009

Journal of Biological Chemistry

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Leptospira interrogans is a pathogenic spirochete that causes disease in both humans and animals. LigB (Leptospiral immunoglobulin-like protein B) contributes to the binding of Leptospira to extracellular matrix proteins such as fibronectin (Fn), fibrinogen, laminin, and collagen. A high affinity Fn-binding region of LigB has been recently localized to LigBCen2, which contains the partial eleventh and full twelfth immunoglobulin-like repeats (LigBCen2R) and 47 amino acids of the non-repeat region (LigBCen2NR) of LigB. In this study, LigBCen2NR was shown to bind to the N-terminal domain (NTD) of Fn (K D ‫؍‬ 379 nM) by an enzyme-linked immunosorbent assay and isothermal titration calorimetry. Interestingly, this sequence was not observed to adopt secondary structure by far UV circular dichroism or by differential scanning calorimetry, in agreement with computer-based secondary structure predictions. A low partition coefficient (K av ) measured with gel permeation chromatography, a high hydrodynamic radius (R h ) measured with dynamic light scattering, and the insensitivity of the intrinsic viscosity to guanidine hydrochloride treatment all suggest that LigBCen2NR possesses an extended and disordered structure. Two-dimensional 15 N-1 H HSQC NMR spectra of intact LigBCen2 in the absence and presence of NTD are consistent with these observations, suggesting the presence of both a ␤-rich region and an unstructured region in LigBCen2 and that the latter of these selectively interacts with NTD. Upon binding to NTD, LigBCen2NR was observed by CD to adopt a ␤-strand-rich structure, suggestive of the known ␤-zipper mode of NTD binding.Leptospira interrogans is a pathogenic spirochete that causes leptospirosis throughout the world, especially in developing countries but also in regions of the United States where it has reemerged (1). Weil's syndrome, a severe form of this disease, is an acute febrile illness associated with multiorgan damage, including liver failure (jaundice), renal failure (nephritis), pulmonary hemorrhage, and meningitis (1), and has a 15% mortality rate if not treated (2). The molecular pathogenesis of leptospirosis is poorly understood, and the bacterial virulence factors involved are largely unknown. Recently, several potential Leptospira virulence factors have been described, including sphingomyelinases, serine proteases, zinc-dependent proteases, and collagenase (3); LipL32 (4); lipopolysaccharide (5); a novel factor H, laminin, and Fn-binding protein (Lsa24 or Len) (6 -8); Loa 22 (9); and Lig (Leptospiral immunoglobulin-like) proteins (10 -12).Lig proteins, including LigA, LigB, and LigC, contain multiple immunoglobulin-like repeat domains (13 in LigA, 12 in LigB and LigC) (10 -12). Interestingly, the first 630 residues, from the N terminus to the first half of the seventh immunoglobulinlike domain, are conserved between LigA and LigB, but the rest of the immunoglobulin-like domains are variable (10 -12) between the two proteins. Also, a non-immunoglobulin-like repeat region found on the C-terminal...

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Section: Identification Of the Binding Sites Of Ntd On Ligbcen2-insupporting

confidence: 76%

Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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Fibronectin Binds to and Induces Conformational Change in a Disordered Region of Leptospiral Immunoglobulin-like Protein B

Lin¹,

Greenwood

Nicholson

et al. 2009

Journal of Biological Chemistry

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“…1B From the early characterization of Fn-binding proteins of S. aureus (3) to more recent studies (18), there is good evidence that the interaction with Fn is multivalent, i.e., between six and nine Fn molecules bind a single copy of FnBPA or FnBPB. We (19) and others (20) have suggested that multivalent binding of Fn to bacterial Fn-binding proteins is likely to play a role in invasion of human cells, and this hypothesis is supported by the observation that bacterial Fn-binding proteins from S. pyogenes also contain multiple Fn-binding sites (4,15). Multivalent binding is rather puzzling however, given the relative sizes of NTD (29-kDa) and FnBPA (40-kDa Fn-binding region).…”

Section: Resultsmentioning

confidence: 83%

“…The total surface area buried is Ϸ4,200 Å 2 . Although it seems clear, based on the relative K D s of FnBR/ 2-5 F1 and peptide/module interactions (4,15), that the full FnBPA-1/ 2-5 F1 and FnBPA-5/ 2-5 F1 interactions can largely be dissected in this way, we have only approximated the relative domain orientations of 3 F1 and 4 F1 in the intact complex. In addition, the FnBRs in the intact bacterial protein are likely to have less flexible N and C termini, which might influence their…”

Section: Resultsmentioning

confidence: 99%

Crystal structures of fibronectin-binding sites from Staphylococcus aureus FnBPA in complex with fibronectin domains

Bingham

Rudino‐Pinera

Meenan

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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120

165

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Staphylococcus aureus can adhere to and invade endothelial cells by binding to the human protein fibronectin (Fn). FnBPA and FnBPB, cell wall-attached proteins from S. aureus, have multiple, intrinsically disordered, high-affinity binding repeats (FnBRs) for Fn. Here, 30 years after the first report of S. aureus/Fn interactions, we present four crystal structures that together comprise the structures of two complete FnBRs, each in complex with four of the N-terminal modules of Fn. Each Ϸ40-residue FnBR forms antiparallel strands along the triple-stranded ␤-sheets of four sequential F1 modules ( 2-5 F1) with each FnBR/ 2-5 F1 interface burying a total surface area of Ϸ4,300 Å 2 . The structures reveal the roles of residues conserved between S. aureus and Streptococcus pyogenes FnBRs and show that there are few linker residues between FnBRs. The ability to form large intermolecular interfaces with relatively few residues has been proposed to be a feature of disordered proteins, and S. aureus/Fn interactions provide an unusual illustration of this efficiency.intrinsic disorder ͉ tandem ␤-zipper ͉ host-pathogen interaction S taphylococcus aureus is a dangerous human pathogen that causes a wide range of debilitating and life-threatening infections (1). Incidence of S. aureus resistance to antibiotics (2) makes the understanding of its mechanisms of pathogenesis imperative. S. aureus/Fn interactions were first reported 30 years ago, and an S. aureus Fn-binding protein was isolated and characterized Ϸ20 years ago (3). Our recent work has dissected the 363-residue C-terminal region of FnBPA into 11 FnBRs (4) (FnBPA1-11; Fig. 1 A and B), six of which bind the NTD (N-terminal domain) of Fn (comprising modules 1-5 F1) with dissociation constants in the nanomolar range (5). The Cterminal region of FnBPB, a second S. aureus Fn-binding protein, is very similar to FnBPA but lacks one of the shorter FnBRs (5). In FnBPA, which also binds fibrinogen, the fibrinogen-and Fn-binding regions (Fig. 1 A) appear to cooperate in disease progression, with the FnBR region being particularly associated with persistence of infection (6). FnBPA/Fn interactions both mediate S. aureus invasion of (7) and activate endothelial cells, evoking both the proinflammatory and procoagulant responses typical of infective endocarditis (8). FnBPAs ability to mediate platelet activation, a key step in thrombus formation, is also likely to play a role in cardiovascular disease (9) and FnBPA has been implicated in cardiac device infections through its ability to mediate S. aureus attachment to implanted prosthetic materials (10). We previously predicted that in Fn-BPA each FnBR binds a string of three or four F1 modules in the NTD of Fn through a longer version of the tandem ␤-zipper mechanism that we discovered in Streptococcus dysgalactiae interactions with 1 F1 2 F1 (4). Results and DiscussionCrystal Structure of FnBPA-1/ 2-5 F1. Fig. 1C shows two F1 module pair/peptide structures that together comprise the structure of the most N-terminal S. aureus FnBR (...

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Protein–Protein Interactions

Kaur¹,

Das²,

Suresh³

2010

Pharmaceutical Sciences Encyclopedia

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Protein–protein interactions are key to several biological pathways and thus are attractive targets for therapeutic intervention. Such approaches are based on a sound assessment of the strong and weak interactions and the protein's secondary or tertiary structures. This article focuses on interactions between some of the important protein–protein pairs and recent successes in developing peptides, peptidomimetics, or small organic molecules as inhibitors of these interactions.

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High Affinity Streptococcal Binding to Human Fibronectin Requires Specific Recognition of Sequential F1 Modules

Cited by 62 publications

References 46 publications

Fibronectin Binds to and Induces Conformational Change in a Disordered Region of Leptospiral Immunoglobulin-like Protein B

Fibronectin Binds to and Induces Conformational Change in a Disordered Region of Leptospiral Immunoglobulin-like Protein B

Crystal structures of fibronectin-binding sites from Staphylococcus aureus FnBPA in complex with fibronectin domains

Protein–Protein Interactions

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