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PDBsum entry 2jjv
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Immune system
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PDB id
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2jjv
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References listed in PDB file
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Key reference
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Title
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Paired receptor specificity explained by structures of signal regulatory proteins alone and complexed with cd47.
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Authors
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D.Hatherley,
S.C.Graham,
J.Turner,
K.Harlos,
D.I.Stuart,
A.N.Barclay.
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Ref.
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Mol Cell, 2008,
31,
266-277.
[DOI no: ]
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PubMed id
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Abstract
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CD47 is a widely distributed cell-surface protein that acts a marker of self
through interactions of myeloid and neural cells. We describe the
high-resolution X-ray crystallographic structures of the immunoglobulin
superfamily domain of CD47 alone and in complex with the N-terminal
ligand-binding domain of signal regulatory protein alpha (SIRPalpha). The
unusual and convoluted interacting face of CD47, comprising the N terminus and
loops at the end of the domain, intercalates with the corresponding regions in
SIRPalpha. We have also determined structures of the N-terminal domains of
SIRPbeta, SIRPbeta(2), and SIRPgamma; proteins that are closely related to
SIRPalpha but bind CD47 with negligible or reduced affinity. These results
explain the specificity of CD47 for the SIRP family of paired receptors in
atomic detail. Analysis of SIRPalpha polymorphisms suggests that these, as well
as the activating SIRPs, may have evolved to counteract pathogen binding to the
inhibitory SIRPalpha receptor.
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Figure 2.
Figure 2. Crystal Structures of the IgSF Domain of CD47
(A) The secondary structure of CD47 is shown above the sequence
of the IgSF domain of human CD47 with arrows and cylinders
representing β sheets and α helices, respectively. The
N-terminal glutamine residue that cyclizes to form a
pyroglutamate is boxed. The cysteine residues that form a
conserved disulphide bond between β sheets are highlighted in
yellow. C15, which forms a disulphide link with the 5
transmembrane helix C-terminal domain of CD47, is starred.
Residues where N-linked glycosylation was observed in at least
one monomer of CD47 are colored magenta.
(B) CD47 (shown as
ribbons) crystallized as a dimer where the G strands are swapped
between pairs of molecules. The structure is color ramped from
blue (N terminus) to red (C terminus), and the strands are
labeled A–G. The three insets show the N-terminal
pyroglutamate, the region between the domains together with the
Mg^2+ that is assumed to facilitate the strand-swap, and one of
the sites of N-linked glycosylation. In all insets, the final
refined model is shown in 2F[O]-F[C] electron density (1.3 σ)
calculated at the end of refinement.
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Figure 3.
Figure 3. The Structure of CD47 in Complex with SIRPα
(A) The structure of CD47 (yellow ribbons) complexed with SIRPα
d1 (blue ribbons). Sites of N-linked glycosylation are shown as
magenta spheres. A schematic representation of the 5
transmembrane helix C-terminal domain of CD47 is shown,
including the proposed disulfide bond between C15 (Gly in our
structure; yellow sphere) and C245. The inset shows a close-up
view of the CD47/SIRPα interaction interface.
(B) The
structure of CD47 in complex with SIRPα (yellow) is almost
indistinguishable from that of CD47 solved in isolation (orange
and gray). Remarkably, the interaction of strand G with the rest
of the CD47 monomer is almost identical regardless of whether it
is strand swapped or not. The inset shows L101 and T102, which
mediate the turn at the tip of the FG loop in the
non-strand-swapped CD47 monomer.
(C) The surface of SIRPα
as viewed by CD47. The molecular surface of SIRPα d1 is shown,
colored by electrostatic potential. Regions of CD47 that
interact with SIRPα are shown as sticks. In (C) and (D), areas
of particular interest are identified by roman numerals (see
[E]) and loop/strand names are shown, with NA denoting the
N-terminal 6 residues of CD47.
(D) The surface of CD47 as
viewed by SIRPα. The molecular surface of CD47 is shown,
colored by electrostatic potential. Loops of SIRPα that
interact with CD47 are shown as sticks.
(E) Selected
portions of the interface. Residues of CD47 (yellow carbon
atoms) and SIRPα (blue carbon atoms) are shown as sticks, and
water molecules are shown as red spheres. The molecular surface
of SIRPα is shown (white, semitransparent). Hydrogen bonds and
salt bridges are shown as orange dashes. The roman numerals of
the panels identify the regions of the interaction on the
molecular surfaces in (C) and (D).
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The above figures are
reprinted
by permission from Cell Press:
Mol Cell
(2008,
31,
266-277)
copyright 2008.
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