Pneumococcus forks out…

New research in the EMBO Journal
provides a first molecular insight into
how Streptococcus pneumoniae binds
to and invades human epithelial cells
— the first step in the pneumococcal
pathogenic process.
Currently, S. pneumoniae infects
approximately 100 million people
each year,with a fatality rate of more
than 10%. In the initial stages of
infection the bacterium adheres to
and enters human nasopharyngeal
epithelial cells and subsequently
escapes to the bloodstream. The
mode of attachment of S. pneumoniae
utilizes a protein on the bacterial
cell surface called choline binding protein
A (CbpA). This adhesin is secreted
by the microorganism and is recaptured
onto the bacterial surface
through interaction with choline moieties.
To invade epithelial cells,CbpA
interacts with a protein — the polymeric
immunoglobulin receptor
(pIgR) — located on the epithelial cell
surface. Although the participation of
CbpA in this process has been known
for some time, the molecular details of
the interaction were not understood.
Now, Elaine Tuomanen, Richard
Kriwacki and colleagues report the
solution structure of one of two
‘repeated’ adhesion domains (R1 and
R2) of CbpA, which are essential for
interaction with pIgR. As these
domains have 78% identity and
exhibit similar biochemical properties,
the authors were also able to use the
solved structure of R2 to model that of
R1. Their analysis of the domains
reveals that both adopt a unique threehelical
raft-like structure with a novel
‘tyrosine fork’ motif positioned in a
loop sequence connecting helices 1
and 2. Phylogenetic analysis of CbpA
sequences from 47 S. pneumoniae
strains revealed that 22 conserved
residues are located in, or in close
proximity to, this loop region. To
further investigate the role of the
R domains in the interaction with
pIgR and the significance of the tyrosine
fork structure, the authors used
surface plasmon resonance and
isothermal titration calorimetry
techniques to analyse the binding
activity of wild-type and sitedirected
mutants of CbpA. These
data confirmed the importance of
some of these conserved residues for
high-affinity binding.
These biochemical data, combined
with the structural-based analysis,
provide an initial insight into a molecular
understanding of CbpA-mediated
bacterial adhesion to pIgR. Future
work will be required to further our
understanding of the mechanism and
to exploit this knowledge in the search
for new antibacterial therapies.
David O’Connell
References and links
ORIGINAL RESEARCH PAPER Lou, R. et al.
Solution structure of choline binding protein A, the
major adhesin of Streptococcus pneumoniae.
EMBO J. 16 December 2004
(doi:10.10138/sj.emboj.7600490)