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Peptide-based Identification of Functional Motifs and their Binding Partners
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Structure and Function Characterization of the a1a2 Motifs of Streptococcus pyogenes M Protein in Human Plasminogen

Adam J H Quek1, Blake A Mazzitelli1, Guojie Wu1

  • 1ARC Centre of Excellence in Advanced Molecular Imaging, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.

Journal of Molecular Biology
|July 12, 2019
PubMed

Insights

Group A Streptococcus uses Plasminogen (Plg)-binding M protein (PAM) to spread. This study reveals how PAM

Area of Science:

  • Microbiology
  • Structural Biology
  • Biochemistry

Background:

  • Group A Streptococcus (GAS) utilizes Plasminogen (Plg)-binding M protein (PAM) as a cell surface receptor crucial for virulence.
  • PAM binding to the Plg kringle 2 (KR2) domain creates a localized proteolytic environment, aiding bacterial dissemination.
  • PAM features two Plg-binding motifs (a1 and a2 repeats) in its dimeric form, with the a2 repeat's role being less understood.

Purpose of the Study:

  • To elucidate the structural basis of the interaction between the a1 and a2 repeats of PAM and the KR2 domain of Plg.
  • To investigate the distinct roles and binding affinities of the a1 and a2 motifs in PAM-Plg complex formation.

Main Methods:

  • X-ray crystallography was employed to determine the 1.7-Å structure of KR2 in complex with a monomeric PAM peptide containing both a1 and a2 motifs.
  • Site-directed mutagenesis and functional assays were utilized to characterize the binding interactions and affinities of the a1 and a2 repeats.

Main Results:

  • The crystal structure revealed simultaneous interactions between the PAM peptide (a1a2 motifs) and two KR2 domains, mediated by lysine isosteres.
  • Mutagenesis and functional studies demonstrated that the a2 repeat exhibits a higher binding affinity for KR2 compared to the a1 repeat.
  • These findings suggest that the a1 and a2 motifs may have specialized functions in the assembly of the PAM-Plg complex.

Conclusions:

  • The a2 repeat of PAM is a stronger binder to Plg's KR2 domain than the a1 repeat.
  • The distinct binding affinities of a1 and a2 motifs suggest they play complementary roles in mediating the overall PAM-Plg interaction.
  • Understanding these molecular interactions provides insights into GAS virulence mechanisms and potential therapeutic targets.
Keywords:
PAMRH motifa1a2 repeatlysine-binding siteplasminogen kringle 2

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