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PDBsum entry 2d10
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Cell adhesion
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PDB id
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2d10
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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 nherf recognition by erm proteins.
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Authors
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S.Terawaki,
R.Maesaki,
T.Hakoshima.
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Ref.
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Structure, 2006,
14,
777-789.
[DOI no: ]
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PubMed id
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Abstract
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The Na+/H+ exchanger regulatory factor (NHERF) is a key adaptor protein involved
in the anchoring of ion channels and receptors to the actin cytoskeleton through
binding to ERM (ezrin/radixin/moesin) proteins. NHERF binds the FERM domain of
ERM proteins, although NHERF has no signature Motif-1 sequence for FERM binding
found in adhesion molecules. The crystal structures of the radixin FERM domain
complexed with the NHERF-1 and NHERF-2 C-terminal peptides revealed a peptide
binding site of the FERM domain specific for the 13 residue motif
MDWxxxxx(L/I)Fxx(L/F) (Motif-2), which is distinct from Motif-1. This Motif-2
forms an amphipathic alpha helix for hydrophobic docking to subdomain C of the
FERM domain. This docking causes induced-fit conformational changes in subdomain
C and affects binding to adhesion molecule peptides, while the two binding sites
are not overlapped. Our studies provide structural paradigms for versatile ERM
linkages between membrane proteins and the cytoskeleton.
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Figure 2.
Figure 2. The FERM-NHERF Interactions
(A) Front (left)
and side (right) views of surface electrostatic potentials of
the radixin FERM domain. The front view is viewed from the same
direction as in Figure 1A. Positive (blue, +14 kT/e) and
negative (red, −14 kT/e) potentials are mapped on the van der
Waals surfaces. The four crystallographic-independent NHERF-1
peptides are shown in tube models (cyan). A side view of the
FERM domain is shown without the NHERF-1 peptide to show two
hydrophobic pockets for the Trp348 and Phe355 side chains from
the NHERF peptide.
(B) A close-up view of the amphipathic
helix of the NHERF-1 peptide (cyan) docked to the groove formed
by the β sandwich of subdomain C (yellow). Hydrogen bonds are
shown with dotted lines. The C-terminal carboxyl group of Leu358
is labeled with CPX.
(C) Schematic diagram of the
interaction between the NHERF-1 peptide (residues 339–358,
cyan main chain bonds) and the FERM domain (brown main chain
bonds) with atom colors: black, C; blue, N; red, O; yellow, S.
Polar contacts are shown with red, dashed lines, and hydrophobic
contacts are indicated by arcs with radiating spokes. A list of
all residues involved in binding either peptide together with
their distances is given in Table S2.
(D) A close-up
view of the superimposed C-terminal region of NHERF-1 (blue)
and NHERF-2 (yellow) peptides bound to the FERM domains. Leu354
and the C-terminal end residue of NHERF-1, Leu358, are replaced
with Ile333 and Phe337 in NHERF-2, respectively. These residues
interact with residues from the FERM domains drawn in cyan
(NHERF-1 bound form) and gray (NHERF-2 bound form).
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Figure 4.
Figure 4. Multiple Binding Modes Found in the FERM Domain
of ERM Proteins
(A) The radixin FERM domain (gray)
complexed with IP3 (Hamada et al., 2000), which is shown as a
ball-and-stick model. Italic labels indicate subdomains A, B,
and C.
(B) The radixin FERM domain complexed with the
ICAM-2 cytoplasmic peptide (magenta) (Hamada et al., 2003).
(C) The radixin FERM domain complexed with the NHERF-1 peptide
(blue; this work).
(D) The moesin FERM domain complexed the
C-tail domain (dark brown) (Pearson et al., 2000).
(E) The
C-tail domain (brown) is superimposed with the NHERF-1 peptide
(blue) bound to the radixin FERM domain (gray).
(F)
Comparison of the C-terminal helix of the NHERF-1 peptide (light
blue) bound to the radixin FERM domain and helix D of the moesin
C-tail domain (brown).
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The above figures are
reprinted
by permission from Cell Press:
Structure
(2006,
14,
777-789)
copyright 2006.
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Secondary reference #1
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Title
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Crystallographic characterization of the radixin ferm domain bound to the c-Terminal region of the human na+/h+-Exchanger regulatory factor (nherf).
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Authors
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S.Terawaki,
R.Maesaki,
K.Okada,
T.Hakoshima.
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Ref.
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Acta Crystallogr D Biol Crystallogr, 2003,
59,
177-179.
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PubMed id
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Secondary reference #2
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Title
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Structural basis of the membrane-Targeting and unmasking mechanisms of the radixin ferm domain.
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Authors
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K.Hamada,
T.Shimizu,
T.Matsui,
S.Tsukita,
T.Hakoshima.
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Ref.
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EMBO J, 2000,
19,
4449-4462.
[DOI no: ]
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PubMed id
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Figure 4.
Figure 4 Subdomain structures of the radixin FERM domain. The
color codes used are light green for radixin subdomains, light
blue for ubiquitin, yellow for acyl-coenzyme A binding protein,
red for the PTB domain and orange for the PH domain. (A)
Superimposition of radixin subdomain A on ubiquitin (PDB code
1UBI, blue). (B) Superimposition of radixin subdomain B on
E.coli acyl-coenzyme A binding protein (yellow, 1ACA). (C)
Superimposition of radixin subdomain C on the IRS-1 PTB domain
(1QQG, red). (D) Superimposition of radixin subdomain C on the
PH domain (1PLS, orange). (E) Comparison of the IP3-binding
sites found in the radixin FERM domain (left), the phospholipase
C  1
PH domain (middle) and the  -spectrin
PH domain (right). Two loops forming the binding site of each PH
domain are colored in blue. The binding site of the radixin FERM
domain is located at the basic cleft between subdomains A (a
ubiquitin-like fold in light green) and C (a PTB-like fold in
light blue) (see text). The N-terminal half of helix  1C
of subdomain C and the protruding loop between strands 3A
and 5A
of subdomain A form the IP3-binding site of the radixin FERM
domain and are colored in blue.
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Figure 5.
Figure 5 Molecular surface properties of the radixin FERM
domain. (A) Surface electrostatic potentials of the radixin FERM
domain viewed from the same direction as in Figure 2A. Positive
(blue) and negative (red) potentials are mapped on the van der
Waals surfaces. The IP3 molecule found in the complex crystal is
shown in a stick model. (B) Surface electrostatic potentials
viewed along the arrow b in (A) to show the basic cleft between
subdomains A and C. The IP3 molecule found in the complex
crystal is shown in a stick model. (C) Surface electrostatic
potentials viewed along arrow c in (A) to show the acidic groove
between subdomains B and C. (D) A backside view of surface
electrostatic potentials seen in (A). The IP3 molecule found in
the complex crystal is shown in a stick model. (E) Conserved
residues of the radixin FERM domain mapped on the molecular
surfaces. A front view of the radixin FERM domain depicted as a
colored molecular surface using a gradient; orange indicates
conserved identical residues and white non-conserved residues,
while lighter shades of orange indicate semi-invariant residues.
A view from the same direction as in (A) and Figure 2A. (F) Back
view of conserved residues of the radixin FERM domain. (G) Front
view of hydrophobic residues of the radixin FERM domain mapped
on the molecular surfaces. (H) Back view of hydrophobic residues
of the radixin FERM domain.
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The above figures are
reproduced from the cited reference
which is an Open Access publication published by Macmillan Publishers Ltd
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Secondary reference #3
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Title
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Structural basis of adhesion-Molecule recognition by erm proteins revealed by the crystal structure of the radixin-Icam-2 complex.
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Authors
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K.Hamada,
T.Shimizu,
S.Yonemura,
S.Tsukita,
S.Tsukita,
T.Hakoshima.
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Ref.
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EMBO J, 2003,
22,
502-514.
[DOI no: ]
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PubMed id
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Figure 1.
Figure 1 Overall structure of the radixin FERM domain bound to
the ICAM-2 tail peptide. (A) Views of the radixin FERM domain
bound to the ICAM-2 peptide by ribbon representations. The
ICAM-2 peptide is shown in blue. The radixin FERM domain
consists of subdomains A (light blue), B (red) and C (brown).
The linkers A -B (residues 83 -95) and B -C (residues 196 -203)
are colored in gray and the C-terminal linker in green. (B) The
ICAM-2 peptide model in a 2F[o]-F[c] electron density map
countered at the 1  level.
The amino acid residues are indicated with labels of one-letter
codes. Labels in parentheses indicate the terminal residues
whose side chains were not defined in the map. (C) The
28-residue peptide synthesized based on the sequence of the
mouse ICAM-2 cytoplasmic tail was used for the structural work.
Basic residues are in blue. This peptide has two basic regions
and a non-polar region between them. The 16 residues of the
peptide defined on the current map are boxed. Key residues in
binding to the radixin FERM domain are underlined (see text).
The short -strand
(residues 7 -10) and one 3[10] helix (resides 12 -15) are
indicated with an arrow and a cylinder.
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Figure 2.
Figure 2 The ICAM-2 tail peptide recognition by the radixin FERM
domain. (A) Surface electrostatic potentials of the radixin FERM
domain viewed from the same direction as in Figure 1A. Positive
(blue, +14 kT/e) and negative (red, -14 kT/e) potentials are
mapped on the van der Waals surfaces. The ICAM-2 peptide found
in the complex crystal is shown in a stick model. The disordered
C-terminal basic region is indicated by an arrow of dotted
lines. (B) The ICAM-2 binding groove on subdomain C is formed
primarily by hydrophobic residues from helix 1C
and strand 5C.
The bound ICAM-2 peptide is shown in a transparency ribbon
model. (C) Schematic representation of the interactions between
the ICAM-2 peptide (blue) and subdomain C (brown). Hydrogen
bonds are shown by broken lines. (D) The ICAM-2 peptide found in
the FERM -ICAM-2 complex is shown in a stick model (light blue)
with their interacting residues from subdomain C (brown).
Hydrogen bonds are shown by dotted lines. (E) A close-up view of
the hydrophobic and hydrogen bonding interactions between the
ICAM-2 peptide and the FERM domain mediated by His288 from
subdomain C.
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The above figures are
reproduced from the cited reference
which is an Open Access publication published by Macmillan Publishers Ltd
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