Lars-Olof Hedén

Extensive sequence homology between IgA receptor and M proteins in Streptococcus pyogenes

Many strains of Streptococcus pyogenes are known to express a receptor for IgA. The complete nucleotide sequence of the gene for such a receptor, protein Arp4, has been determined. The deduced amino acid sequence of 386 residues includes a signal sequence of 41 amino acids and a putative membrane anchor region, both of which are homologous to similar regions in other streptococcal surface proteins. The processed form of the IgA receptor has a length of 345 amino acids and a calculated molecular weight of 39544. The N‐terninal sequence of the processed form is different from that previously found for a similar IgA receptor isolated from a S. pyogenes strain of type M60. The sequence of protein Arp4 shows extensive homology to the C‐terminal half of streptococcal M proteins, but not to the streptococcal IgG receptor protein G or staphlyococcal protein A. Apart from the membrane anchor, this homology includes a sequence of 119 amino acid residues containing three repeated units and a 54‐residue sequence without repeats. The protein expressed in Escherichia coli is found in the periplasmic space, in which it constitutes the major protein. Protein Arp4 is the first example of a surface protein that has both immunoglobulin‐binding capacity and structural features characteristic of M proteins. And structural features characteristic of MJ proteins.

Duplication of a DNA sequence homologous to genes for immunoglobulin receptors and M proteins in Streptococcus pyogenes

The nucleotide sequence of an open reading frame of 355 amino acids downstream of the IgA-binding protein gene arp4 in Streptococcus pyogenes M-type 4 has been determined. Analysis of the deduced amino acid sequence for the open reading frame shows an extensive homology to streptococcal M proteins and immunoglobulin binding proteins. Expression of the open reading frame has not been detected and the function may be as a genetic reservoir in the generation of new immunoglobulin receptors and antigenic variants of M proteins.

Conserved and variable regions in protein Arp, the IgA receptor of Streptococcus pyogenes

The streptococcal M protein family, a number of cell surface molecules that interact with the human immune system, can be divided into two major classes, A and C, characterized by different types of repeats in the central part of the molecule. Class A and class C molecules are known to have a variable N-terminal region and a more conserved C-terminal region, but little is known about the mechanisms that give rise to this structural variation. In this report, we show that two variants of protein Arp, an IgA receptor in class C of the M protein family, have virtually identical signal sequences and C-terminal halves, but unrelated N-terminal sequences. Comparison of the sequences of the two genes and their flanking regions also demonstrates the presence of well-defined variable and conserved regions. Our results strongly suggest that the N-terminal sequence variation between the two variants of protein Arp was generated through an intergenic recombination event, rather than through intragenic recombination or accumulation of mutations.

A proline-rich region with a highly periodic sequence in Streptococcal beta protein adopts the polyproline II structure and is exposed on the bacterial surface.

Proline-rich regions have been identified in many surface proteins of pathogenic streptococci and staphylococci. These regions have been suggested to be located in cell wall-spanning domains and/or to be required for surface expression of the protein. Because little is known about these regions, which are found in extensively studied and biologically important surface proteins, we characterized the proline-rich region in one such protein, the beta protein of group B streptococci. The proline-rich region in beta, designated the XPZ region, has a proline at every third position, and the sequence is highly periodic in other respects. Immunochemical analysis showed that the XPZ region was not associated with the cell wall but was exposed on the bacterial surface. Moreover, characterization of a beta mutant lacking the XPZ region demonstrated that this region was not required for surface expression of the beta protein. Comparison of the XPZ region in different beta proteins showed that it varied in size but always retained the typical sequence periodicity. Circular dichroism spectroscopy indicated that the XPZ region had the structure of a polyproline II helix, an extended and solvent-exposed structure with exactly three residues per turn. Because of the three-residue sequence periodicity in the XPZ region, it is expected to be amphipathic and to have distinct nonpolar and polar surfaces. This study identified a proline-rich structure with unique properties that is exposed on the surface of an important human pathogen.

Human C4BP Binds to the Hypervariable N-Terminal Region of Many Members in the Streptococcal M Protein Family

Characterization of many molecules in the streptococcal M protein family has shown that they all have similar overall structure, with a variable N-terminal part and a conserved C-terminal part, the latter including a central repeat region.7 Moreover, the variable N-terminal part can be divided into a hypervariable region, encompassing ∼50 amino acid residues and located most N-terminally, and a semi-conserved region.

Streptococcal IgA Receptors

Cell wall proteins that bind immunoglobulins have been found in bacteria of several different species (Table 1). Two of these Ig receptors, staphylococcal protein A and streptococcal protein G, are able to bind IgG and therefore are commonly used as immunological tools, and have been extensively characterized.1 Several proteins that bind Ig of other classes than IgG are also known and have been studied in detail (Table 1). Thus, two different IgA receptors have been isolated from streptococci, and a protein that binds IgD has been isolated from the Gram-negative bacterium Haemophilus influenzae. In addition to these receptors, which preferrentially bind to the Fc region of immunoglobulins, a protein that binds to κ light chains has been isolated from the anaerobic bacterium Peptococcus magnus. The biological role of these Ig-binding proteins is still unclear, but it is commonly believed that they are important for the ability of the bacteria to cause disease in man.