PAM, a novel plasminogen-binding protein from Streptococcus pyogenes.

Berge, Andreas; Sjöbring, Ulf

doi:10.1016/s0021-9258(19)74408-1

Cited by 212 publications

(32 citation statements)

References 41 publications

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“…This is a critical finding in understanding how skintrophic strains of GAS initiates an infection at the wound site and progresses to dissemination. In some strains, GAS is known to form complexes with fibrinogen (Fg) via its particular M-Protein (46) and, in the case of the AP53R + S − strain of GAS, Fg does not directly bind to PAM, but can bind to the AP53R + S − /PAM/Pg complex, since hPg binds to PAM via hPg kringle (K)2 and Fg binds to hPg via K1, K4, and K5 (11,13,(47)(48)(49). Once GAS is trapped by Fg, different leukocytes are recruited to the wound in order to eliminate the bacteria.…”

Section: Discussionmentioning

confidence: 99%

“…A critical determinant for skin-trophic strains of GAS dissemination during infection is mediated by two GAS virulence factors, human plasminogen (hPg)-binding M-protein (PAM) and streptokinase (SK2b) (6)(7)(8)(9)(10). PAM is an M-protein variant that displays high affinity binding to human plasminogen (hPg) (9,(11)(12)(13)(14). The secreted protein SK2b, from GAS subsequently activates PAM-bound hPg to hPm through cleavage of the R 561 V 562 peptide bond and removal of a N-terminal 77-residue activation peptide (6,11,(15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

“…PAM is an M-protein variant that displays high affinity binding to human plasminogen (hPg) (9,(11)(12)(13)(14). The secreted protein SK2b, from GAS subsequently activates PAM-bound hPg to hPm through cleavage of the R 561 V 562 peptide bond and removal of a N-terminal 77-residue activation peptide (6,11,(15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

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Group A Streptococcus-Induced Activation of Human Plasminogen Is Required for Keratinocyte Wound Retraction and Rapid Clot Dissolution

Zhong

Nguyen

et al. 2021

Front. Cardiovasc. Med.

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Invasive outcomes of Group A Streptococcus (GAS) infections that involve damage to skin and other tissues are initiated when these bacteria colonize and disseminate via an open wound to gain access to blood and deeper tissues. Two critical GAS virulence factors, Plasminogen-Associated M-Protein (PAM) and streptokinase (SK), work in concert to bind and activate host human plasminogen (hPg) in order to create a localized proteolytic environment that alters wound-site architecture. Using a wound scratch assay with immortalized epithelial cells, real-time live imaging (RTLI) was used to examine dynamic effects of hPg activation by a PAM-containing skin-trophic GAS isolate (AP53R+S−) during the course of infection. RTLI of these wound models revealed that retraction of the epithelial wound required both GAS and hPg. Isogenic AP53R+S− mutants lacking SK or PAM highly attenuated the time course of retraction of the keratinocyte wound. We also found that relocalization of integrin β1 from the membrane to the cytoplasm occurred during the wound retraction event. We devised a combined in situ-based cellular model of fibrin clot-in epithelial wound to visualize the progress of GAS pathogenesis by RTLI. Our findings showed GAS AP53R+S− hierarchically dissolved the fibrin clot prior to the retraction of keratinocyte monolayers at the leading edge of the wound. Overall, our studies reveal that localized activation of hPg by AP53R+S−via SK and PAM during infection plays a critical role in dissemination of bacteria at the wound site through both rapid dissolution of the fibrin clot and retraction of the keratinocyte wound layer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Group A Streptococcus-Induced Activation of Human Plasminogen Is Required for Keratinocyte Wound Retraction and Rapid Clot Dissolution

Zhong

Nguyen

et al. 2021

Front. Cardiovasc. Med.

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“…Other extracellular proteins, such as Skizzle from GBS, and surface-associated Plg-binding bacterial products (often referred to as bacterial Plg receptors), rely instead on external activators, such as host-derived uPA or tPA, for conversion of bound Plg into Pl ( Wiles et al., 2010 ; Peetermans et al., 2016 ). Bacterial Plg receptors include “moonlighting” cytoplasmic enzymes, such as α-enolase and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) ( Winram and Lottenberg, 1996 ; Pancholi and Fischetti, 1998 ; Bergmann et al, 2003 ; Seifert et al., 2003 ; Boël et al., 2005 ) as well as specialized lipoproteins or cell wall proteins, such as Plg-binding streptococcal M- and M-like proteins ( Berge and Sjobring, 1993 ; Wistedt et al., 1995 ; Ringdahl and Sjobring, 2000 ; Bhattacharya et al., 2012 ). A common feature of bacterial surface Plg receptors is their ability to interact with LBS, as indicated by inhibition of these interactions using free lysine or EACA.…”

Section: Introductionmentioning

confidence: 99%

Lysine Residues in the MK-Rich Region Are Not Required for Binding of the PbsP Protein From Group B Streptococci to Plasminogen

Coppolino

Romeo

Pietrocola

et al. 2021

Front. Cell. Infect. Microbiol.

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Binding to plasminogen (Plg) enables bacteria to associate with and invade host tissues. The cell wall protein PbsP significantly contributes to the ability of group B streptococci, a frequent cause of invasive infection, to bind Plg. Here we sought to identify the molecular regions involved in the interactions between Plg and PbsP. The K4 Kringle domain of the Plg molecule was required for binding of Plg to whole PbsP and to a PbsP fragment encompassing a region rich in methionine and lysine (MK-rich domain). These interactions were inhibited by free L-lysine, indicating the involvement of lysine binding sites in the Plg molecule. However, mutation to alanine of all lysine residues in the MK-rich domain did not decrease its ability to bind Plg. Collectively, our data identify a novel bacterial sequence that can interact with lysine binding sites in the Plg molecule. Notably, such binding did not require the presence of lysine or other positively charged amino acids in the bacterial receptor. These data may be useful for developing alternative therapeutic strategies aimed at blocking interactions between group B streptococci and Plg.

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“…Structurally, all known PAMs are domain‐assembled proteins composed consecutively of a 41‐residue NH 2 ‐terminal signal peptide, a hypervariable region (HVR), A‐, B‐, C‐, and D‐domains, a Pro/Gly‐rich region, a LPXTG motif recognized by sortase A, a COOH‐terminal transmembrane anchor, and a very short C‐terminal extracellular region (Fischetti et al, 1988 ; Smeesters et al, 2010 ). In Pattern D strains, PAM subdomains, viz., the a1 and/or a2 repeats of its A‐domain, specifically bind to the kringle‐2 module of hPg (K2 hPg ; Berge & Sjobring, 1993 ; Rios‐Steiner et al, 2001 ). According to the amino acid sequence and the number of tandem repeats in the PAM A‐domain, we previously categorized PAMs into three classes: Class I and Class III (both containing a1‐ and a2‐repeats) and Class II (a2‐repeat only; Qiu et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Binding of the kringle‐2 domain of human plasminogen to streptococcal PAM‐type M‐protein causes dissociation of PAM dimers

Ayinuola

Qiu

et al. 2021

MicrobiologyOpen

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The direct binding of human plasminogen (hPg), via its kringle‐2 domain (K2 hPg ), to streptococcal M‐protein (PAM), largely contributes to the pathogenesis of Pattern D Group A Streptococcus pyogenes (GAS). However, the mechanism of complex formation is unknown. In a system consisting of a Class II PAM from Pattern D GAS isolate NS88.2 (PAM NS88.2 ), with one K2 hPg binding a‐repeat in its A‐domain, we employed biophysical techniques to analyze the mechanism of the K2 hPg /PAM NS88.2 interaction. We show that apo‐PAM NS88.2 is a coiled‐coil homodimer (M.Wt. ~80 kDa) at 4°C–25°C, and is monomeric (M.Wt. ~40 kDa) at 37°C, demonstrating a temperature‐dependent dissociation of PAM NS88.2 over a narrow temperature range. PAM NS88.2 displayed a single tight binding site for K2 hPg at 4°C, which progressively increased at 25°C through 37°C. We isolated the K2 hPg /PAM NS88.2 complexes at 4°C, 25°C, and 37°C and found molecular weights of ~50 kDa at each temperature, corresponding to a 1:1 (m:m) K2 hPg /PAM NS88.2 monomer complex. hPg activation experiments by streptokinase demonstrated that the hPg/PAM NS88.2 monomer complexes are fully functional. The data show that PAM dimers dissociate into functional monomers at physiological temperatures or when presented with the active hPg module (K2 hPg ) showing that PAM is a functional monomer at 37°C.

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PAM, a novel plasminogen-binding protein from Streptococcus pyogenes.

Cited by 212 publications

References 41 publications

Group A Streptococcus-Induced Activation of Human Plasminogen Is Required for Keratinocyte Wound Retraction and Rapid Clot Dissolution

Group A Streptococcus-Induced Activation of Human Plasminogen Is Required for Keratinocyte Wound Retraction and Rapid Clot Dissolution

Lysine Residues in the MK-Rich Region Are Not Required for Binding of the PbsP Protein From Group B Streptococci to Plasminogen

Binding of the kringle‐2 domain of human plasminogen to streptococcal PAM‐type M‐protein causes dissociation of PAM dimers

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