Crystal structure of the C2 fragment of streptococcal protein G in complex with the Fc domain of human IgG.
BACKGROUND
Streptococcal protein G comprises two or three domains that bind to the constant Fc region of most mammalian immunoglobulin Gs (IgGs). Protein G is functionally related to staphylococcal protein A, with which it shares neither sequence nor structural homology.


RESULTS
To understand the competitive binding of these two proteins to the Fc region, the crystal structure of a single Ig-binding domain of streptococcal protein G was determined at 3.5 A resolution in complex with the Fc fragment of human IgG and compared with the structures of protein A:Fc and protein G:Fab complexes. Protein G binds to the interface between the second and third heavy chain constant domains of Fc, which is roughly the same binding site used by protein A. Protein G comprises one alpha-helix packed onto a four-stranded beta-sheet. Residues from protein G that are involved in binding are situated within the C-terminal part of the alpha-helix, the N-terminal part of the third beta-strand and the loop region connecting these two structural elements. The identified Fc-binding region of protein G agrees well with both biochemical and NMR spectroscopic data. However, the Fc-binding helices of protein G and protein A are not superimposable.


CONCLUSIONS
Protein G and protein A have developed different strategies for binding to Fc. The protein G:Fc complex involves mainly charged and polar contacts, whereas protein A and Fc are held together through non-specific hydrophobic interactions and a few polar interactions. Several residues of Fc are involved in both the protein G:Fc and the protein A:Fc interaction, which explains the competitive binding of the two proteins. The apparent differences in their Fc-binding activities result from additional unique interactions.
Sauer-Eriksson
A E
AE
Department of Molecular Biology, Uppsala University, Sweden.
Kleywegt
G J
GJ
Uhlén
M
M
Jones
T A
TA
D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D001483:Base Sequence; D018360:Crystallography, X-Ray; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000378:metabolism; D007074:Immunoglobulin G / Q000737:chemistry* / Q000378:metabolism*; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D013205:Staphylococcal Protein A / Q000737:chemistry / Q000378:metabolism; D013291:Streptococcus / Q000737:chemistry*
D001426:Bacterial Proteins; C029152:G-substrate; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D009419:Nerve Tissue Proteins; D013205:Staphylococcal Protein A