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PDBsum entry 2a55
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Immune system
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PDB id
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2a55
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References listed in PDB file
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Key reference
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Title
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Human c4b-Binding protein, Structural basis for interaction with streptococcal m protein, A major bacterial virulence factor.
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Authors
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H.T.Jenkins,
L.Mark,
G.Ball,
J.Persson,
G.Lindahl,
D.Uhrin,
A.M.Blom,
P.N.Barlow.
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Ref.
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J Biol Chem, 2006,
281,
3690-3697.
[DOI no: ]
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PubMed id
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Abstract
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Human C4b-binding protein (C4BP) protects host tissue, and those pathogens able
to hijack this plasma glycoprotein, from complement-mediated destruction. We now
show that the first two complement control protein (CCP) modules of the C4BP
alpha-chain, plus the four residues connecting them, are necessary and
sufficient for binding a bacterial virulence factor, the Streptococcus pyogenes
M4 (Arp4) protein. Structure determination by NMR reveals two tightly coupled
CCP modules in an elongated arrangement within this region of C4BP. Chemical
shift perturbation studies demonstrate that the N-terminal, hypervariable region
of M4 binds to a site including strand 1 of CCP module 2. This interaction is
accompanied by an intermodular reorientation within C4BP. We thus provide a
detailed picture of an interaction whereby a pathogen evades complement.
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Figure 4.
Titration of C4BP12 with M4-N. Overlay of five ^15N-^1H HSQC
spectra of 20 μmC4BP12 (20 mm NaOAc, pH 6.0, 37 °C) with
increasing concentrations of M4-N. Colors are as follows: black,
0 μm M4-N; red, 10 μm M4-N; purple, 25 μm M4-N; blue, 50 μm
M4-N; navy, 100 μm M4-N (all concentrations are for the dimer).
Cross-peaks from residues altered in the mutagenesis studies are
labeled.
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Figure 5.
Surface representations of C4BP12. The closest to mean
structure of residues 1-124 is shown. A, surface representation,
indicating residues that show chemical shift changes upon M4-N
binding. Blue, small combined chemical shift difference (see
below); red, large chemical shift difference, unable to track
cross-peak. Residues for which no ^NH shift information could be
obtained (either proline residues or due to overlap in the HSQC
spectra) are colored gray. B, electrostatic surface potential,
Calculated using the Adaptive Poisson-Boltzmann Solver (49)
plug-in within PyMOL: red is negative charge, and blue is
positive charge. A range of -5/+5 kT was used. Those amino acids
substituted in a mutagenesis study are marked. C, same view of
the surface (transparent with backbone trace underneath) with
residues that show chemical shift changes upon M4-N binding
colored according to position: yellow, close to the interface
(the chemical shift of these could be influenced by intermodular
reorientation or direct contact); cyan, residues away from the
interface likely to be in direct contact with M4-N. The aromatic
side chains of Tyr^37, Tyr^62, and Phe^84 are shown in
space-fill representation. D, sequence of C4BP12 illustrating
the ^NH chemical shift changes on addition of M4-N. The residues
are colored as follows: black, no apparent change (combined
chemical shift difference √((Δδ^NH)^2 + (Δδ^15N/5)^2 <
0.08 ppm); gray, data missing; blue, small shift (combined
chemical shift difference of >0.08 ppm, <0.2 ppm but able to
trace peak movement); red, large shift (unable to track peak).
All figures produced using PyMOL (http://www.pymol.org).
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2006,
281,
3690-3697)
copyright 2006.
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