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Microbiology Department Journal Club
Structural basis for Duffy recognition by the malaria parasite Duffybinding–like domain
Singh SK, Hora R, Belrhali H, Chitnis CE, Sharma A
Nature 439: 741-744, 2005
Structural basis for the EBA-175 erythrocyte invasion pathway of
themalaria parasite Plasmodium falciparum
Tolia NH, Enemark EJ, Sim KL, Joshua-Tor L
Cell 122: 183-193, 2005
Background
Plasmodium causes Malaria which affects more than 500 million people
and kills about two million annually.
P. falciparum is the most prevalent; P. vivax less so; P. knowlesi is the
simian counterpart.
Infection is caused by sporozoites entering into the host bloodstream
after a female Anopheles mosquito bite and infecting hepatocytes; the
hepatocytes rupture and release thousands of merozoites each of which
can invade an erythrocyte, thus initiating the asexual erythrocytic stage
of the parasite’s life cycle.
All pathological and clinical manifestations of the disease are caused by
this critical invasion step.
Background, continued…
Binding to the host endothelium is accomplished through the function of
a common adhesion molecule found in two families of parasite ligands.
EBL (erythrocyte binding ligand) family of erythrocyte invasion ligands
and the var/PfEMP1 (P. falciparum erythrocyte membrane protein 1)
family of cytoadherence ligands
This adhesive domain, called the Duffy-binding like (DBL) domain was
first described as part of the Duffy Binding Protein (DBP), an important
invasion ligand of both P. vivax and P. knowlesi for erythrocytes.
DBL domains contribute to both invasion and cytoadherence and are one
of the most versatile and polymorphic adhesive molecules.
X-ray crystallography structures of the DBL domains from two wellstudied EBL ligands, the P. knowlesi DBP (PkDBP) and the P.
falciparum EBA-175, have been published.
EBP, EBA, PfEMP, …
Nature 439: 741-744, 2005
EBL, DBL, DBP, PfEMP, …
Cell 122: 183-193, 2005
erythrocyte binding domain (critical)
PkDBP alignments
Nature 439: 741-744, 2005
EBA-175 alignments
Cell 122: 183-193, 2005
PkDBP structure (3 Å)
11 alpha helices, unique fold, three subdomains
Nature 439: 741-744, 2005
EBA-175 structure (2.3 Å)
Cell 122: 183-193, 2005
Binding
DBL domains bind several substrates and have different binding sites,
sometimes involving dimerisation.
EBA-175 and PkDBP bind different receptors on the erythrocyte surface.
PkDBL (and PvDBL) bind the host DARC (Duffy antigen receptor for
chemokines); mutagenesis data available.
EBA-175, BAEBL, and JSEBL all can bind sialic acid residues, but each
recognises different erythrocyte sialoglycoproteins; receptor for EBA175 is human RBC receptor glycophorin A. Redundant pathways means
that EBA-175 is not essential.
X-ray structure of EBA-175 was solved with sialic acid derivative,
alpha-2,3,sialyllactoase to identify the glycan binding site; additional
mutagenesis experiments were performed.
PkDBL binding
Nature 439: 741-744, 2005
PvDBL binding
polymorphic residues in
field isolates; immune system
evasion
binding site
“just-in-time” release
and binding to receptor
Nature 439: 741-744, 2005
PkDBL binding
SD2
DARC binding
site
antigenic
site
SD2
SD1
antigenic
site
EBA-175 binding
Cell 122: 183-193, 2005
Model for EBA-175 region 2 binding to glycophorin A
Cell 122: 183-193, 2005
Superimposed DBLs (within 2 Å of each other)
DARC binding
site
glycan
binding
sites
A treasure of insights
A treasure of insights
DARC binding
site
glycan
binding
site
Conclusions – insights from x-ray structures
Different sites target different substrates and receptors in different DBL
domains
Interplay between sequence conservation and variation to evade immune
evasion
For PvDBL, target the DBL-DARC interaction for therapeutics
(conserved)
For EBA-175, target the glycan binding sites; distrupt dimersation and/or
DBL domain interactions