ArticleThe Journal of biological chemistry2014
Dimerization is not a determining factor for functional high affinity human plasminogen binding by the group A streptococcal virulence factor PAM and is mediated by specific residues within the PAM a1a2 domain.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 22 citations in OpenAlex.
- Hydrophobic residues in the D-domain of a plasminogen-binding M-protein modulate α-helicity, oligomerization, and surface anchoring in Streptococcus pyogenes.Protein science : a publication of the Protein Society · 2025Article
- Group aMicrobiology spectrum · 2025Article
- Interactions between membrane-bound streptococcal alpha-enolase and human plasminogen captured through cryogenic-electron microscopy.Frontiers in molecular biosciences · 2025Article
- A High-Throughput Small-Angle X-ray Scattering Assay to Determine the Conformational Change of Plasminogen.International journal of molecular sciences · 2023Article
- Inactivation of the lysine binding sites of human plasminogen (hPg) reveals novel structural requirements for the tight hPg conformation, M-protein binding, and rapid activation.Frontiers in molecular biosciences · 2023Article
- Relationships Between Plasminogen-Binding M-Protein and Surface Enolase for Human Plasminogen Acquisition and Activation inFrontiers in microbiology · 2022Article
- Group AFrontiers in cardiovascular medicine · 2021Article
- The M Protein of Streptococcus pyogenes Strain AP53 Retains Cell Surface Functional Plasminogen Binding after Inactivation of the Sortase A Gene.Journal of bacteriology · 2020Article
- Solution structural model of the complex of the binding regions of human plasminogen with its M-protein receptor from Streptococcus pyogenes.Journal of structural biology · 2019Article
- Structure and Function Characterization of the a1a2 Motifs of Streptococcus pyogenes M Protein in Human Plasminogen Binding.Journal of molecular biology · 2019Article
- Variations in the secondary structures of PAM proteins influence their binding affinities to human plasminogen.Journal of structural biology · 2019Article
- Contributions of different modules of the plasminogen-binding Streptococcus pyogenes M-protein that mediate its functional dimerization.Journal of structural biology · 2018Article
- Conformationally organized lysine isosteres inThe Journal of biological chemistry · 2017Article
- Variable region in streptococcal M-proteins provides stable binding with host fibrinogen for plasminogen-mediated bacterial invasion.The Journal of biological chemistry · 2017Article
- Tissue tropisms in group A Streptococcus: what virulence factors distinguish pharyngitis from impetigo strains?Current opinion in infectious diseases · 2016Review
- Direct Host Plasminogen Binding to Bacterial Surface M-protein in Pattern D Strains of Streptococcus pyogenes Is Required for Activation by Its Natural Coinherited SK2b Protein.The Journal of biological chemistry · 2015Article
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6 authors at 2 institutions in 2 countries.
Funding
Abstract
A emm53 subclass of Group A Streptococcus pyogenes (GAS) interacts tightly with human plasma plasminogen (hPg) and plasmin (hPm) via the kringle 2 (K2hPg) domain of hPg/hPm and the N-terminal a1a2 regions of a GAS coiled-coil M-like protein (PAM). Previous studies have shown that a monomeric PAM fragment, VEK30 (residues 97-125 + Tyr), interacted specifically with isolated K2hPg. However, the binding strength of VEK30 (KD = 56 nm) was ∼60-fold weaker than that of full-length dimeric PAM (KD = 1 nm). To assess whether this attenuated binding was due to the inability of VEK30 to dimerize, we defined the minimal length of PAM required to dimerize using a series of peptides with additional PAM residues placed at the NH2 and COOH termini of VEK30. VEK64 (PAM residues 83-145 + Tyr) was found to be the smallest peptide that adopted an α-helical dimer, and was bound to K2hPg with nearly the same affinity as PAM (KD = 1-2 nm). However, addition of two PAM residues (Arg(126)-His(127)) to the COOH terminus of VEK30 (VEK32) maintained a monomeric peptidic structure, but exhibited similar K2hPg binding affinity as full-length dimeric PAM. We identified five residues in a1a2 (Arg(113), His(114), Glu(116), Arg(126), His(127)), mutation of which reduced PAM binding affinity for K2hPg by ∼ 1000-fold. Replacement of these critical residues by Ala in the GAS genome resulted in reduced virulence, similar to the effects of inactivating the PAM gene entirely. We conclude that rather than dimerization of PAM, the five key residues in the binding domain of PAM are essential to mediate the high affinity interaction with hPg, leading to increased GAS virulence.
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