Crystal structure of group A streptococcus Mac-1: insight into dimer-mediated specificity for recognition of human IgG.
Group A Streptococcus secretes cysteine proteases named Mac-1 and Mac-2 that mediate host immune evasion by targeting both IgG and Fc receptors. Here, we report the crystal structures of Mac-1 and its catalytically inactive C94A mutant in two different crystal forms. Despite the lack of sequence homology, Mac-1 adopts the canonical papain fold. Alanine mutations at the active site confirmed the critical residues involved in a papain-like catalytic mechanism. Mac-1 forms a symmetric dimer in both crystal forms and displays the unique dimer interface among papain superfamily members. Mutations at the dimer interface resulted in a significant reduction in IgG binding and catalysis, suggesting that the dimer contributes to both IgG specificity and enzyme cooperativity. A tunnel observed at the dimer interface constitutes a target for designing potential Mac-1-specific antimicrobial agents. The structures also offer insight into the functional difference between Mac-1 and Mac-2.
Structural Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 12441 Parklawn Drive, Rockville, Maryland 20852, USA.
Johnson
J
Agniswamy
Michal J
MJ
Nagiec
Mengyao
M
Liu
Peter
P
Schuck
James M
JM
Musser
Peter D
PD
Sun
D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D002384:Catalysis; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D019281:Dimerization; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry* / Q000378:metabolism; D016023:Integrins / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010206:Papain / Q000737:chemistry; D016415:Sequence Alignment; D013297:Streptococcus pyogenes / Q000201:enzymology*; D040681:Structural Homology, Protein; D013379:Substrate Specificity
D001426:Bacterial Proteins; D007074:Immunoglobulin G; D016023:Integrins; C442815:Mac-1-like protein, Streptococcus; D003546:Cysteine Endopeptidases; D010206:Papain