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Title: Structure of dimerized radixin FERM domain suggests a novel masking motif in C-terminal residues 295–304

Abstract

The crystal structure of dimerized radixin FERM domain has been determined. It was found that the adhesion molecule-binding site of one molecule is masked by the C-terminal residues of the other molecule. ERM (ezrin/radixin/moesin) proteins bind to the cytoplasmic tail of adhesion molecules in the formation of the membrane-associated cytoskeleton. The binding site is located in the FERM (4.1 and ERM) domain, a domain that is masked in the inactive form. A conventional masking motif, strand 1 (residues 494–500 in radixin), has previously been identified in the C-terminal tail domain. Here, the crystal structure of dimerized radixin FERM domains (residues 1–310) is presented in which the binding site of one molecule is occupied by the C-terminal residues (residues 295–304, strand 2) of the other molecule. The residues contain a conserved motif that is compatible with that identified in the adhesion molecules. The residues might serve as a second masking region in the inactive form of ERM proteins.

Authors:
;  [1];  [1];  [2]
  1. Structural Biology Laboratory, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192 (Japan)
  2. (Japan)
Publication Date:
OSTI Identifier:
22356351
Resource Type:
Journal Article
Resource Relation:
Journal Name: Acta Crystallographica. Section F; Journal Volume: 62; Journal Issue: Pt 4; Other Information: PMCID: PMC2222584; PMID: 16582480; PUBLISHER-ID: tb5004; OAI: oai:pubmedcentral.nih.gov:2222584; Copyright (c) International Union of Crystallography 2006; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United Kingdom
Language:
English
Subject:
75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND SUPERFLUIDITY; ADHESION; CRYSTAL STRUCTURE; MASKING; MEMBRANES; MOLECULES; PROTEINS

Citation Formats

Kitano, Ken, Yusa, Fumie, Hakoshima, Toshio, E-mail: hakosima@bs.naist.jp, and CREST, Japan Science and Technology Agency. Structure of dimerized radixin FERM domain suggests a novel masking motif in C-terminal residues 295–304. United Kingdom: N. p., 2006. Web. doi:10.1107/S1744309106010062.
Kitano, Ken, Yusa, Fumie, Hakoshima, Toshio, E-mail: hakosima@bs.naist.jp, & CREST, Japan Science and Technology Agency. Structure of dimerized radixin FERM domain suggests a novel masking motif in C-terminal residues 295–304. United Kingdom. doi:10.1107/S1744309106010062.
Kitano, Ken, Yusa, Fumie, Hakoshima, Toshio, E-mail: hakosima@bs.naist.jp, and CREST, Japan Science and Technology Agency. Sat . "Structure of dimerized radixin FERM domain suggests a novel masking motif in C-terminal residues 295–304". United Kingdom. doi:10.1107/S1744309106010062.
@article{osti_22356351,
title = {Structure of dimerized radixin FERM domain suggests a novel masking motif in C-terminal residues 295–304},
author = {Kitano, Ken and Yusa, Fumie and Hakoshima, Toshio, E-mail: hakosima@bs.naist.jp and CREST, Japan Science and Technology Agency},
abstractNote = {The crystal structure of dimerized radixin FERM domain has been determined. It was found that the adhesion molecule-binding site of one molecule is masked by the C-terminal residues of the other molecule. ERM (ezrin/radixin/moesin) proteins bind to the cytoplasmic tail of adhesion molecules in the formation of the membrane-associated cytoskeleton. The binding site is located in the FERM (4.1 and ERM) domain, a domain that is masked in the inactive form. A conventional masking motif, strand 1 (residues 494–500 in radixin), has previously been identified in the C-terminal tail domain. Here, the crystal structure of dimerized radixin FERM domains (residues 1–310) is presented in which the binding site of one molecule is occupied by the C-terminal residues (residues 295–304, strand 2) of the other molecule. The residues contain a conserved motif that is compatible with that identified in the adhesion molecules. The residues might serve as a second masking region in the inactive form of ERM proteins.},
doi = {10.1107/S1744309106010062},
journal = {Acta Crystallographica. Section F},
number = Pt 4,
volume = 62,
place = {United Kingdom},
year = {Sat Apr 01 00:00:00 EST 2006},
month = {Sat Apr 01 00:00:00 EST 2006}
}
  • The merlin-1 tumor suppressor is encoded by the Neurofibromatosis-2 (Nf2) gene and loss-of-function Nf2 mutations lead to nervous system tumors in man and to several tumor types in mice. Merlin is an ERM (ezrin, radixin, moesin) family cytoskeletal protein that interacts with other ERM proteins and with components of cell-cell adherens junctions (AJs). Merlin stabilizes the links of AJs to the actin cytoskeleton. Thus, its loss destabilizes AJs, promoting cell migration and invasion, which in Nf2{sup +/-} mice leads to highly metastatic tumors. Paradoxically, the 'closed' conformation of merlin-1, where its N-terminal four-point-one, ezrin, radixin, moesin (FERM) domain binds tomore » its C-terminal tail domain, directs its tumor suppressor functions. Here we report the crystal structure of the human merlin-1 head domain when crystallized in the presence of its tail domain. Remarkably, unlike other ERM head-tail interactions, this structure suggests that binding of the tail provokes dimerization and dynamic movement and unfurling of the F2 motif of the FERM domain. We conclude the 'closed' tumor suppressor conformer of merlin-1 is in fact an 'open' dimer whose functions are disabled by Nf2 mutations that disrupt this architecture.« less
  • The radixin FERM domain has been crystallized in complex with CD43 and PSGL-1 peptides. Diffraction data sets were collected from the complexes to 2.9 and 2.8 Å resolution, respectively. Radixin is a member of the ERM proteins that cross-link plasma membranes and actin filaments. The FERM domains located in the N-terminal regions of ERM proteins are responsible for membrane association through direct interaction with the cytoplasmic tails of integral membrane proteins. Here, crystals of the radixin FERM domain bound to the cytoplasmic peptides of two adhesion molecules, CD43 and PSGL-1, have been obtained. Crystals of the radixin FERM domain boundmore » to CD43 belong to space group P4{sub 3}22, with unit-cell parameters a = b = 68.72, c = 201.39 Å, and contain one complex in the crystallographic asymmetric unit. Crystals of the radixin FERM domain bound to PSGL-1 belong to space group P2{sub 1}2{sub 1}2{sub 1}, with unit-cell parameters a = 80.74, b = 85.73, c = 117.75 Å, and contain two complexes in the crystallographic asymmetric unit. Intensity data sets were collected to a resolution of 2.9 Å for the FERM–CD43 complex and 2.8 Å for the FERM–PSGL-1 complex.« less
  • The radixin FERM domain complexed with the CD44 cytoplasmic tail peptide has been crystallized. A diffraction data set from the complex was collected to 2.1 Å. CD44 is an important adhesion molecule that specifically binds hyaluronic acid and regulates cell–cell and cell–matrix interactions. Increasing evidence has indicated that CD44 is assembled in a regulated manner into the membrane–cytoskeletal junction, a process that is mediated by ERM (ezrin/radixin/moesin) proteins. Crystals of a complex between the radixin FERM domain and the C-terminal cytoplasmic region of CD44 have been obtained. The crystal of the radixin FERM domain bound to the CD44 cytoplasmic tailmore » peptide belongs to space group P2{sub 1}2{sub 1}2{sub 1}, with unit-cell parameters a = 62.70, b = 66.18, c = 86.22 Å, and contain one complex in the crystallographic asymmetric unit. An intensity data set was collected to a resolution of 2.1 Å.« less