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PDBsum entry 2al6
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References listed in PDB file
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Key reference
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Title
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Crystal structure of the ferm domain of focal adhesion kinase.
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Authors
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D.F.Ceccarelli,
H.K.Song,
F.Poy,
M.D.Schaller,
M.J.Eck.
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Ref.
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J Biol Chem, 2006,
281,
252-259.
[DOI no: ]
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PubMed id
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Abstract
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Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that localizes to
focal adhesions in adherent cells. Through phosphorylation of proteins assembled
at the cytoplasmic tails of integrins, FAK promotes signaling events that
modulate cellular growth, survival, and migration. The amino-terminal region of
FAK contains a region of sequence homology with band 4.1 and
ezrin/radixin/moesin (ERM) proteins termed a FERM domain. FERM domains are found
in a variety of signaling and cytoskeletal proteins and are thought to mediate
intermolecular interactions with partner proteins and phospholipids at the
plasma membrane and intramolecular regulatory interactions. Here we report two
crystal structures of an NH2-terminal fragment of avian FAK containing the FERM
domain and a portion of the regulatory linker that connects the FERM and kinase
domains. The tertiary folds of the three subdomains (F1, F2, and F3) are similar
to those of known FERM structures despite low sequence conservation. Differences
in the sequence and relative orientation of the F3 subdomain alters the nature
of the interdomain interface, and the phosphoinositide binding site found in ERM
family FERM domains is not present in FAK. A putative protein interaction site
on the F3 lobe is masked by the proximal region of the linker. Additionally, in
one structure the adjacent Src SH3 and SH2 binding sites in the linker associate
with the surfaces of the F3 and F1 lobes, respectively. These structural
features suggest the possibility that protein interactions of the FAK FERM
domain can be regulated by binding of Src kinases to the linker segment.
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Figure 4.
FIGURE 4. Detailed view of the F3 lobe highlighting the
linker interaction. A, ribbon diagram of the FAK F3 lobe with
the proximal portion of the linker shown in stick form and
colored magenta. The details of this interaction are shown
schematically in panel C. B, the radixin F3 lobe (yellow) bound
to a peptide representing the cytoplasmic tail of ICAM-2 (gray).
C, schematic detailing the interactions of the linker with the
putative ligand binding groove on the F3 lobe. Linker residues
are indicated in magenta, FERM domain residues in cyan. Dashed
lines indicate hydrogen bond interactions and semicircles
indicate hydrophobic interactions. Note that the linker also
contacts the F1 lobe as indicated.
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Figure 5.
FIGURE 5. Portions of the FERM kinase linker including the
Src SH3 binding site and the Tyr397 autophosphorylation site are
tethered across the surface of the F1 and F3 subdomains in the
FAK405 structure. A, ribbon and transparent surface
representation of the FAK FERM domain. The Src SH3 binding site
is shown in green (residues 363-375) and the Tyr397-containing
segment (residues 394-403) is colored in pink. B, detail of the
interactions between the Src SH3-binding site and the surface of
F3. Hydrogen bonds between the RXXPXXP motif (residues Arg368 to
Pro374) and the F3 lobe are indicated by dashed lines and
involve the side chains of Gln303 and Gln317 on the F3 lobe. C,
details of the interaction between the FAK autophosphorylation
Tyr397 segment and the F1 lobe. Hydrogen bonds are indicated
with dashed lines and involve the side chains of Glu403 with
His41 and Ser54 bonds. Tyr397 is surface exposed and not
phosphorylated in the structure.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2006,
281,
252-259)
copyright 2006.
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