RESEARCH HIGHLIGHTS Nature Reviews Microbiology | AOP, published online 17 February 2014; doi:10.1038/nrmicro3233
B AC T E R I A L P H Y S I O LO GY
Mycoplasmal protein binds antibodies
NPG
protein M bound to different mononclonal antibodies, irrespective of their specificity
Bacteria have evolved antibodybinding proteins, such as staphylococcal protein A and streptococcal protein G, to evade host immunity. A study now identifies a new antibodybinding protein in Mycoplasma spp. with a unique structure that enables it to broadly bind to human antibodies and inhibit their engagement with antigens. Chronic infections often lead to B cell proliferation and increased antibody production and sometimes even to the development of B cell tumours. To test whether infection with Mycoplasma spp. potentially has the same effect, the authors studied patients with multiple myeloma, which is an antibody-producing cancer of B cells. They tested the reactivity of serum from these patients with cellular extracts from several Mycoplasma species. Interestingly, the antibodies contained in the sera bound to a protein (termed protein M) from the extracts of those species that infect humans but did not react with extracts from nonhuman Mycoplasma spp. Furthermore, sera from
healthy donors also reacted with protein M, which indicated that many different antibodies recognize this protein and that the reaction might not be antigen specific. Indeed, purified protein M bound to different mononclonal antibodies, irrespective of their specificity. Mass spectrometry of the antibody-binding component of Mycoplasma genitalium extract identified protein M as protein MG281, which is a 556 amino acid transmembrane protein of unknown function. Bioinformatics analysis showed that homologues of protein M are found in other Mycoplasma spp., such as Mycoplasma pneumoniae, Mycoplasma iowae and Mycoplasma gallisepticum. Co-crystal structures of protein M fragments (that contained residues 74–482) and the variable, antigenbinding fragments (Fabs) of antibodies that were specific for HIV‑1 and influenza virus revealed that a large protein M domain binds to conserved residues on the Fab surface, mostly via hydrogen bonds and salt bridges. This binding mode differs from other bacterial antibody-binding proteins, which all have multiple, small binding domains and target other areas of the
NATURE REVIEWS | MICROBIOLOGY
antibody; in fact, protein M does not resemble any other known protein. The authors propose that protein M blocks access of the antibody to the antigen by binding and masking large parts of the Fab surface. Indeed, IgGs that were pre-incubated with protein M could no longer bind to their cognate antigens — for example, influenza virus hemagglutinin and HIV‑1 glycoprotein 120. Furthermore, whereas other antibody-binding proteins often target only certain antibody subtypes, purified protein M bound with high affinity to all subtypes of human IgG and even to IgG from other species. The functional role of protein M in Mycoplasma spp. is currently unclear; other bacterial antibodybinding proteins function as virulence factors, but such a role has not yet been established for protein M. However, as protein M can bind to antibodies with broad specificity and high affinity, it is expected to become a valuable research tool. Ursula Hofer ORIGINAL RESEARCH PAPER Grover, R. K. et al. A structurally distinct human mycoplasma protein that generically blocks antigen–antibody union. Science 343, 656–660 (2014)
VOLUME 12 | APRIL 2014 © 2014 Macmillan Publishers Limited. All rights reserved
B AC T E R I A L P H Y S I O LO GY
Mycoplasmal protein binds antibodies
NPG
protein M bound to different mononclonal antibodies, irrespective of their specificity
Bacteria have evolved antibodybinding proteins, such as staphylococcal protein A and streptococcal protein G, to evade host immunity. A study now identifies a new antibodybinding protein in Mycoplasma spp. with a unique structure that enables it to broadly bind to human antibodies and inhibit their engagement with antigens. Chronic infections often lead to B cell proliferation and increased antibody production and sometimes even to the development of B cell tumours. To test whether infection with Mycoplasma spp. potentially has the same effect, the authors studied patients with multiple myeloma, which is an antibody-producing cancer of B cells. They tested the reactivity of serum from these patients with cellular extracts from several Mycoplasma species. Interestingly, the antibodies contained in the sera bound to a protein (termed protein M) from the extracts of those species that infect humans but did not react with extracts from nonhuman Mycoplasma spp. Furthermore, sera from
healthy donors also reacted with protein M, which indicated that many different antibodies recognize this protein and that the reaction might not be antigen specific. Indeed, purified protein M bound to different mononclonal antibodies, irrespective of their specificity. Mass spectrometry of the antibody-binding component of Mycoplasma genitalium extract identified protein M as protein MG281, which is a 556 amino acid transmembrane protein of unknown function. Bioinformatics analysis showed that homologues of protein M are found in other Mycoplasma spp., such as Mycoplasma pneumoniae, Mycoplasma iowae and Mycoplasma gallisepticum. Co-crystal structures of protein M fragments (that contained residues 74–482) and the variable, antigenbinding fragments (Fabs) of antibodies that were specific for HIV‑1 and influenza virus revealed that a large protein M domain binds to conserved residues on the Fab surface, mostly via hydrogen bonds and salt bridges. This binding mode differs from other bacterial antibody-binding proteins, which all have multiple, small binding domains and target other areas of the
NATURE REVIEWS | MICROBIOLOGY
antibody; in fact, protein M does not resemble any other known protein. The authors propose that protein M blocks access of the antibody to the antigen by binding and masking large parts of the Fab surface. Indeed, IgGs that were pre-incubated with protein M could no longer bind to their cognate antigens — for example, influenza virus hemagglutinin and HIV‑1 glycoprotein 120. Furthermore, whereas other antibody-binding proteins often target only certain antibody subtypes, purified protein M bound with high affinity to all subtypes of human IgG and even to IgG from other species. The functional role of protein M in Mycoplasma spp. is currently unclear; other bacterial antibodybinding proteins function as virulence factors, but such a role has not yet been established for protein M. However, as protein M can bind to antibodies with broad specificity and high affinity, it is expected to become a valuable research tool. Ursula Hofer ORIGINAL RESEARCH PAPER Grover, R. K. et al. A structurally distinct human mycoplasma protein that generically blocks antigen–antibody union. Science 343, 656–660 (2014)
VOLUME 12 | APRIL 2014 © 2014 Macmillan Publishers Limited. All rights reserved
