A local α-helix drives structural evolution of streptococcal M-protein affinity for host human plasminogen.
Plasminogen-binding group A streptococcal M-protein (PAM) is a signature surface virulence factor of specific strains of Group A Streptococcus pyogenes (GAS) and is an important tight binding protein for human plasminogen (hPg). After activation of PAM-bound hPg to the protease, plasmin (hPm), GAS cells develop invasive surfaces that are critical for their pathogenicity. PAMs are helical dimers in solution, which are sensitive to temperature changes over a physiological temperature range. We previously categorized PAMs into three classes (I-III) based on the number and nature of short tandem α-helical repeats (a1 and a2) in their NH2-terminal A-domains that dictate interactions with hPg/hPm. Class II PAMs are special cases since they only contain the a2-repeat, while Class I and Class III PAMs encompass complete a1a2-repeats. All dimeric PAMs tightly associate with hPg, regardless of their categories, but monomeric Class II PAMs bind to hPg much weaker than their Class I and Class III monomeric counterparts. Additionally, since the A-domains of Class II PAMs comprise different residues from other PAMs, the issue emerges as to whether Class II PAMs utilize different amino acid side chains for interactions with hPg. Herein, through NMR-refined structural analyses, we elucidate the atomic-level hPg-binding mechanisms adopted by two representative Class II PAMs. Furthermore, we develop an evolutionary model that explains from unique structural perspectives why PAMs develop variable A-domains with regard to hPg-binding affinity.
['Qiu|Cunjia|C|', 'Yuan|Yue|Y|', 'Lee|Shaun W|SW|', 'Ploplis|Victoria A|VA|', 'Castellino|Francis J|FJ|']
D000942:Antigens, Bacterial D001425:Bacterial Outer Membrane Proteins D001426:Bacterial Proteins D002352:Carrier Proteins D019143:Evolution, Molecular D005341:Fibrinolysin D000076662:Host Microbial Interactions D062105:Molecular Docking Simulation D010958:Plasminogen D011485:Protein Binding D000072756:Protein Conformation, alpha-Helical D054730:Protein Interaction Domains and Motifs D013297:Streptococcus pyogenes D037521:Virulence Factors
plasminogen Gram-positive bacteria NMR spectroscopy bacterial receptor protein interactions protein–ligand binding