Structure and Function Characterization of the a1a2 Motifs of Streptococcus pyogenes M Protein in Human Plasminogen Binding
Autor: | Yue Yuan, Martina L. Sanderson-Smith, Adam J. Quek, Devadharshini Jeevarajah, James C. Whisstock, Ruby H. P. Law, Paul J. Conroy, Yetunde A. Ayinuola, Guojie Wu, Blake A. Mazzitelli, Eleanor W. W. Leung, Gordon J. Lloyd, Francis J. Castellino, Tom T. Caradoc-Davies |
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Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
Myeloma protein
Streptococcus pyogenes Lysine Cell Amino Acid Motifs Peptide medicine.disease_cause Crystallography X-Ray Article 03 medical and health sciences Structure-Activity Relationship 0302 clinical medicine Bacterial Proteins Protein Domains Structural Biology Cell surface receptor medicine Humans Amino Acid Sequence Molecular Biology Pathogen 030304 developmental biology chemistry.chemical_classification 0303 health sciences Chemistry Protein Stability Mutagenesis Plasminogen medicine.anatomical_structure Biochemistry 030217 neurology & neurosurgery Protein Binding |
Zdroj: | J Mol Biol |
Popis: | Plasminogen (Plg)-binding M protein (PAM) is a group A streptococcal cell surface receptor that is crucial for bacterial virulence. Previous studies revealed that, by binding to the kringle 2 (KR2) domain of host Plg, the pathogen attains a proteolytic microenvironment on the cell surface that facilitates its dissemination from the primary infection site. Each of the PAM molecules in their dimeric assembly consists of two Plg binding motifs (called the a1 and a2 repeats). To date, the molecular interactions between the a1 repeat and KR2 have been structurally characterized, whereas the role of the a2 repeat is less well defined. Here, we report the 1.7-A x-ray crystal structure of KR2 in complex with a monomeric PAM peptide that contains both the a1 and a2 motifs. The structure reveals how the PAM peptide forms key interactions simultaneously with two KR2 via the high-affinity lysine isosteres within the a1a2 motifs. Further studies, through combined mutagenesis and functional characterization, show that a2 is a stronger KR2 binder than a1, suggesting that these two motifs may play discrete roles in mediating the final PAM-Plg assembly. |
Databáze: | OpenAIRE |
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