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PDBsum entry 2mcy
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Immune system
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PDB id
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2mcy
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References listed in PDB file
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Key reference
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Title
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Using mutagenesis and structural biology to map the binding site for the plasmodium falciparum merozoite protein pfrh4 on the human immune adherence receptor.
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Authors
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H.J.Park,
M.Guariento,
M.Maciejewski,
R.Hauhart,
W.H.Tham,
A.F.Cowman,
C.Q.Schmidt,
H.D.Mertens,
M.K.Liszewski,
D.E.Hourcade,
P.N.Barlow,
J.P.Atkinson.
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Ref.
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J Biol Chem, 2014,
289,
450-463.
[DOI no: ]
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PubMed id
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Abstract
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To survive and replicate within the human host, malaria parasites must invade
erythrocytes. Invasion can be mediated by the P. falciparum reticulocyte-binding
homologue protein 4 (PfRh4) on the merozoite surface interacting with complement
receptor type 1 (CR1, CD35) on the erythrocyte membrane. The PfRh4 attachment
site lies within the three N-terminal complement control protein modules (CCPs
1-3) of CR1, which intriguingly also accommodate binding and regulatory sites
for the key complement activation-specific proteolytic products, C3b and C4b.
One of these regulatory activities is decay-accelerating activity. Although
PfRh4 does not impact C3b/C4b binding, it does inhibit this convertase
disassociating capability. Here, we have employed ELISA, co-immunoprecipitation,
and surface plasmon resonance to demonstrate that CCP 1 contains all the
critical residues for PfRh4 interaction. We fine mapped by homologous
substitution mutagenesis the PfRh4-binding site on CCP 1 and visualized it with
a solution structure of CCPs 1-3 derived by NMR and small angle x-ray
scattering. We cross-validated these results by creating an artificial
PfRh4-binding site through substitution of putative PfRh4-interacting residues
from CCP 1 into their homologous positions within CCP 8; strikingly, this
engineered binding site had an ∼30-fold higher affinity for PfRh4 than the
native one in CCP 1. These experiments define a candidate site on CR1 by which
P. falciparum merozoites gain access to human erythrocytes in a non-sialic
acid-dependent pathway of merozoite invasion.
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