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PDBsum entry 2zpy
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Cell adhesion
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PDB id
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2zpy
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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 for cd44 recognition by erm proteins.
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Authors
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T.Mori,
K.Kitano,
S.Terawaki,
R.Maesaki,
Y.Fukami,
T.Hakoshima.
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Ref.
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J Biol Chem, 2008,
283,
29602-29612.
[DOI no: ]
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PubMed id
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Abstract
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CD44 is an important adhesion molecule that functions as the major hyaluronan
receptor which mediates cell adhesion and migration in a variety of
physiological and pathological processes. Although full activity of CD44
requires binding to ERM (ezrin/radixin/moesin) proteins, the CD44 cytoplasmic
region, consisting of 72 amino acid residues, lacks the Motif-1 consensus
sequence for ERM binding found in intercellular adhesion molecule (ICAM)-2 and
other adhesion molecules of the immunoglobulin superfamily. Ultracentrifugation
sedimentation studies and circular dichroism measurements revealed an extended
monomeric form of the cytoplasmic peptide in solution. The crystal structure of
the radixin FERM domain complexed with a CD44 cytoplasmic peptide reveals that
the KKKLVIN sequence of the peptide forms a beta strand followed by a short loop
structure that binds subdomain C of the FERM domain. Like Motif-1 binding, the
CD44 beta strand binds the shallow groove between strand beta5C and helix
alpha1C and augments the beta sheet beta5C-beta7C from subdomain C. Two
hydrophobic CD44 residues, Leu and Ile, are docked into a hydrophobic pocket
with the formation of hydrogen bonds between Asn of the CD44 short loop and loop
beta4C-beta5C from subdomain C. This binding mode resembles that of NEP (neutral
endopeptidase 24.11) rather than ICAM-2. Our results reveal a characteristic
versatility of peptide recognition by the FERM domains from ERM proteins,
suggest a possible mechanism by which the CD44 tail is released from the
cytoskeleton for nuclear translocation by regulated intramembrane proteolysis,
and provide a structural basis for Smad1 interactions with activated CD44 bound
to ERM protein.
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Figure 2.
Crystal structure of the FERM-CD44 complex. A, ribbon
representations of the radixin FERM domain complexed with the
CD44 cytoplasmic peptide (blue). The radixin FERM domain
comprises three subdomains: A (residues 3-82 in green), B
(residues 96-195 in red), and C (residues 204-297 in yellow).
Linkers A-B (residues 83-95) and B-C (residues 196-203) are
colored gray. B, surface electrostatic potentials of the FERM
domain and a close-up view of the CD44 cytoplasmic peptide
docked into the groove formed between helix α1C and strand β5C
of subdomain C. The peptide is shown as a stick model (labeled
with one-letter codes), and the four side chain-binding sites
(S1--S4) for the bound β strand of CD44 and the deep
hydrophobic pocket (P1) are labeled and indicated with yellow
dashed circles. Site S4 adjoins pocket P1. C, a stick model of
the CD44 cytoplasmic peptide is shown in the omit electron
density map for the CD44 cytoplasmic peptide at the contour
level of 1σ.
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Figure 4.
Comparison of ICAM-2, NEP, and CD44 peptides bound to the
FERM domain. Shown is superposition of ICAM-2 (magenta) from the
FERM-ICAM-2 complex (28) and NEP (green) from the FERM-NEP
complex (31) on the FERM-CD44 complex. The N-terminal extensions
of ICAM-2 and CD44 or the C terminus of NEP that would be linked
to the transmembrane helix in the plasmamembrane are indicated
with dotted lines.
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The above figures are
reprinted
from an Open Access publication published by the ASBMB:
J Biol Chem
(2008,
283,
29602-29612)
copyright 2008.
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