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PDBsum entry 2i9a
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References listed in PDB file
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Key reference
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Title
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Structural basis of interaction between urokinase-Type plasminogen activator and its receptor.
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Authors
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C.Barinka,
G.Parry,
J.Callahan,
D.E.Shaw,
A.Kuo,
K.Bdeir,
D.B.Cines,
A.Mazar,
J.Lubkowski.
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Ref.
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J Mol Biol, 2006,
363,
482-495.
[DOI no: ]
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PubMed id
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Abstract
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Recent studies indicate that binding of the urokinase-type plasminogen activator
(uPA) to its high-affinity receptor (uPAR) orchestrates uPAR interactions with
other cellular components that play a pivotal role in diverse
(patho-)physiological processes, including wound healing, angiogenesis,
inflammation, and cancer metastasis. However, notwithstanding the wealth of
biochemical data available describing the activities of uPAR, little is known
about the exact mode of uPAR/uPA interactions or the presumed conformational
changes that accompany uPA/uPAR engagement. Here, we report the crystal
structure of soluble urokinase plasminogen activator receptor (suPAR), which
contains the three domains of the wild-type receptor but lacks the cell-surface
anchoring sequence, in complex with the amino-terminal fragment of
urokinase-type plasminogen activator (ATF), at the resolution of 2.8 A. We
report the 1.9 A crystal structure of free ATF. Our results provide a structural
basis, represented by conformational changes induced in uPAR, for several
published biochemical observations describing the nature of uPAR/uPA
interactions and provide insight into mechanisms that may be responsible for the
cellular responses induced by uPA binding.
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Figure 2.
Figure 2. A representation of ATF binding to uPAR. Domains
D^I (amino acid residues 1–93), D^II (residues 94–191) and
D^III (residues 192–277) of suPAR are shown in yellow, blue,
and red, respectively; KD (residues 47–132) is in green, GFD
(residues 10–46) in magenta. (a) A cartoon representation of
the suPAR[2345]/ATF complex. The individual β-strands of
suPAR[2345] are labeled according to Llinas et al.^30 and Low et
al.^31 Domain D^I: βIA (residues 2–8), βIB (13–17), βIC
(24–33), βID (38–45), βIE (53–59), and βIF (63–70);
domain D^II: βIIA (94–100), βIIB (112–115), βIIC
(122–129), βIID (143–149), βIIE (156–161), and βIIF
(163–171); domain D^III: βIIIA (195–199), βIIIB
(211–214), βIIIC (222–229), βIIID (236–243), and βIIIE
(259–267). Contacts between the domains are mediated
via interactions βIE and βIID (domains D^I and D^II), βIIE
and βIIID (domains D^II and D^III). (b) The ATF (cartoon
representation) binds to the central cavity of suPAR[2345]
(surface representation) and the Ω-loop (Cys19–Cys31,
ball-and-sticks) is primarily responsible for the high-affinity
binding. Residues of suPAR[2345] interacting with ATF are in
cyan.
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Figure 5.
Figure 5. Repositioning of the “integrin-interacting”
loop (Trp129–Arg142) in suPAR[2345] upon ATF binding.
Interactions between amino acid residues Cys19–Lys23 of the
ATF and Pro138–Asp140 of suPAR[2345] leads to bending of the
loop towards the central cavity of the receptor. (a) The
complexes, suPAR[2345]/ATF (domains D^I, D^II and D^III colored
yellow, blue and red, respectively) and suPAR/AE147 (shown in
gray), were aligned on the basis of the corresponding C^α atoms
of domain D^I only. GFD is shown as a combination of
ball-and-sticks and semi-transparent surface. The βIIC-βIID
hairpin is in cartoon representation and its residues
interacting with GFD as ball-and-sticks. (b) A detailed view of
residues engaged in the interactions between strands βIIC and
βIID of suPAR[2345] and the Ω-loop of ATF. The Ω-loop is
shown in surface representation and the interacting residues
contributed by domain D^II are shown as balls-and-sticks. Note
the major movement of the βIIC-βIID hairpin caused by
interactions with the Ω-loop. In both structures, amino acid
residues 132 through 136 of suPAR are missing.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2006,
363,
482-495)
copyright 2006.
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