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PDBsum entry 2h45
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Cell adhesion, structural protein
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PDB id
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2h45
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References listed in PDB file
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Key reference
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Title
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Interdomain association in fibronectin: insight into cryptic sites and fibrillogenesis.
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Authors
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I.Vakonakis,
D.Staunton,
L.M.Rooney,
I.D.Campbell.
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Ref.
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EMBO J, 2007,
26,
2575-2583.
[DOI no: ]
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PubMed id
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Note In the PDB file this reference is
annotated as "TO BE PUBLISHED".
The citation details given above were identified by an automated
search of PubMed on title and author
names, giving a
perfect match.
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Abstract
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The process by which fibronectin (FN), a soluble multidomain protein found in
tissue fluids, forms insoluble fibrillar networks in the extracellular matrix is
poorly understood. Cryptic sites found in FN type III domains have been
hypothesized to function as nucleation points, thereby initiating
fibrillogenesis. Exposure of these sites could occur upon tension-mediated
mechanical rearrangement of type III domains. Here, we present the solution
structures of the second type III domain of human FN ((2)FNIII), and that of an
interaction complex between the first two type III domains ((1-2)FNIII). The two
domains are connected through a long linker, flexible in solution. A weak but
specific interdomain interaction maintains (1-2)FNIII in a closed conformation
that associates weakly with the FN N-terminal 30 kDa fragment (FN30 kDa).
Disruption of the interdomain interaction by amino-acid substitutions
dramatically enhances association with FN30 kDa. Truncation analysis of
(1-2)FNIII reveals that the interdomain linker is necessary for robust
(1-2)FNIII-FN30 kDa interaction. We speculate on the importance of this
interaction for FN function and present a possible mechanism by which tension
could initiate fibrillogenesis.
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Figure 3.
Figure 3 (A, B) Representative structures of the two different
^1-2FNIII forms present in the structure calculation. Occupancy
of form A in the final ensemble was 78%, whereas that of form B
was 22%. Side chains for two residues, K669 and D767, involved
in an electrostatic interaction in form A but not form B, are
shown. D767 is also involved in electrostatic interactions with
K672 in population A, and participates in an extended hydrogen
bond and electrostatics network on the ^1FNIII binding interface
of ^2FNIII. The interdomain linker is schematically represented
as a dashed line. (C, D) ^1-2FNIII structure. Shown here are:
the final 39-structure ensemble of ^1-2FNIII structures
displaying (C) or omitting (D) the flexible ^1FNIII–^2FNIII
linker. Secondary structure elements are colored cyan and purple
for ^1FNIII and ^2FNIII, respectively.
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Figure 5.
Figure 5 Possible fibrillogenesis mechanism: FN molecules exist
in solution, with the ^1-2FNIII domain pair in closed
conformation, likely interacting with the FN N-terminus as part
of a larger globular structure (A). Under tension, the FN
globular structure and the ^1FNIII–^2FNIII interaction are
disrupted (B, C). This allows the ^1-2FNIII open conformation to
strongly associate with the N-terminus of other FN molecules (C)
and, along with the disulfide crosslinks at the FN C-terminus,
create FN fibrils. The different domain types of FN are shown in
gold (FNI), purple (FNII) or cyan (FNIII). The different FN
fragments shown correspond to: FN30 kDa, ^1-5FNI; gelatin
binding domain, ^6FNI-^1-2FNII-^7-9FNI.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
EMBO J
(2007,
26,
2575-2583)
copyright 2007.
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