PDBsum entry 2yvc

Cell adhesion

PDB id: 2yvc

Contents

Protein chains

295 a.a. *

17 a.a. *

Ligands

MET-ASP-ILE-THR-ASP-ILE-ASN

MET-ASP-ILE-THR-ASP

* Residue conservation analysis

PDB id:

2yvc

Name:

Cell adhesion

Title:

Crystal structure of the radixin ferm domain complexed with the nep cytoplasmic tail

Structure:

Radixin. Chain: a, b, c. Fragment: ferm domain. Synonym: esp10. Engineered: yes. Neprilysin. Chain: d, e, f. Fragment: cytoplasmic tail. Synonym: neutral endopeptidase 24.11, neutral endopeptidase, nep,

Source:

Mus musculus. Mouse. Organism_taxid: 10090. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: this sequence occurs naturally in mouse.

Resolution:

3.20Å R-factor: 0.234 R-free: 0.267

Authors:

S.Terawaki,K.Kitano,T.Hakoshima

Key ref:

S.Terawaki et al. (2007). Structural basis for type II membrane protein binding by ERM proteins revealed by the radixin-neutral endopeptidase 24.11 (NEP) complex. J Biol Chem, 282, 19854-19862. PubMed id: 17459884 DOI: 10.1074/jbc.M609232200

Date:

11-Apr-07 Release date: 24-Apr-07

Protein chains

P26043  (RADI_MOUSE) -  Radixin from Mus musculus

Seq: 583 a.a.

Struc: 295 a.a.

Protein chain

Q61391  (NEP_MOUSE) -  Neprilysin from Mus musculus

Seq: 750 a.a.

Struc: 17 a.a.

Enzyme reactions

• Enzyme class: Chain F: E.C.3.4.24.11 - neprilysin.
• Reaction: Preferential cleavage at the amino group of hydrophobic residues in insulin, casein, hemoglobin, and a number of other proteins and polypeptides.
• Cofactor: Zn(2+)

DOI no: 10.1074/jbc.M609232200

J Biol Chem 282:19854-19862 (2007)

PubMed id: 17459884

Structural basis for type II membrane protein binding by ERM proteins revealed by the radixin-neutral endopeptidase 24.11 (NEP) complex.

S.Terawaki, K.Kitano, T.Hakoshima.

ABSTRACT

ERM (Ezrin/Radixin/Moesin) proteins mediate formation of membrane-associated cytoskeletons by simultaneously binding actin filaments and the C-terminal cytoplasmic tails of adhesion molecules (type I membrane proteins). ERM proteins also bind neutral endopeptidase 24.11 (NEP), a type II membrane protein, even though the N-terminal cytoplasmic tail of NEP possesses the opposite peptide polarity to that of type I membrane proteins. Here, we determined the crystal structure of the radixin FERM (Four point one and ERM) domain complexed with the N-terminal NEP cytoplasmic peptide. In the FERM-NEP complex, the amphipathic region of the peptide forms a beta strand followed by a hairpin that bind to a shallow groove of FERM subdomain C. NEP binding is stabilized by beta-beta interactions and docking of the NEP hairpin into the hydrophobic pocket of subdomain C. Whereas the binding site of NEP on the FERM domain overlaps with the binding site of intercellular adhesion molecule (ICAM)-2, NEP lacks the Motif-1 sequence conserved in ICAM-2 and related adhesion molecules. The NEP hairpin, although lacking the typical inter-chain hydrogen bond but is stabilized by hydrogen bonds with the main chain and side chains of subdomain C, directs the C-terminal basic region of the NEP peptide away from the groove and toward the membrane. The overlap of the binding sites on subdomain C for NEP and Motif-1 adhesion molecules such as CD44 provides the structural basis for the suppression of cell adhesion through interaction between NEP and ERM proteins.

Selected figure(s)

Figure 2.
FIGURE 2. Structure of the radixin-NEP complex. Ribbon representations of the radixin FERM domain complexed with the NEP cytoplasmic peptide (blue). The residue numbers of both NEP peptide ends are indicated. The N-terminal polar residues (1-5) were not defined in the current map. The radixin FERM domain consists of three subdomains: A (82 N-terminal residues 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.

Figure 6.
FIGURE 6. Comparison of FERM-binding modes of NEP and ICAM-2 peptides bound to the FERM domain. A, comparison of NEP and ICAM-2 cytoplasmic peptides bound to the radixin FERM domain. Superposition of the ICAM-2 cytoplasmic tail (magenta) in the FERM-ICAM-2 complex on the NEP (blue)-FERM (gray) complex. The N-terminal (ICAM-2) or C-terminal (NEP) regions that would be linked to the trans-membrane helix is indicated with dotted lines. B, schematic representation of ERM proteins bound to type I and II membrane proteins on the plasma membrane. ERM proteins have the N-terminal FERM (blue triangle) and C-terminal F-actin binding (red block) domains. The FERM domain of membrane-recruited ERM proteins binds the cytoplasmic tails, whereas the C-terminal domain binds actin filaments (cyan). The FERM domain binds the juxtamembrane region (a yellow arrow, Motif-1) of the C-terminal cytoplasmic tail of type I membrane proteins such as adhesion molecules CD44 and ICAM-2. In the case of type II membrane protein NEP, the FERM domain binds the N-terminal cytoplasmic tail at a distal region (a pink arrow, Motif-1 ) from the membrane. These two binding interactions interfere with one another by direct competition for binding to the same groove of the FERM domain.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2007, 282, 19854-19862) copyright 2007.

Figures were selected by an automated process.