Structure of the ERM Protein Moesin Reveals the FERM Domain Fold Masked by an Extended Actin Binding Tail Domain

Pearson, M.A.; Reczek, David; Bretscher, Anthony; Karplus, P. Andrew

doi:10.1016/s0092-8674(00)80836-3

Cited by 562 publications

(636 citation statements)

References 66 publications

(5 reference statements)

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“…To then further verify that changes in FRET efficiency are dependent on interdomain binding, a phosphorylation-mimicking mutant of a key regulatory phosphorylation site, Thr564, was used. Phosphorylation of this C-terminal threonine contributes to weakening of the FERM-CTD interaction presumably by both electrostatic and steric effects (14). As expected, the emission spectrum of the ECFP-FERM-CTD T564E -EYFP complex showed a corresponding reduction of the magnitude of the YFP specific emission peak.…”

Section: Structuralsupporting

confidence: 73%

“…The tunable switch model involves relatively subtle thermodynamic changes between the conformational states, and both closed and open conformations can coexist in a population. While physical interaction of the isolated FERM domain and CTD produces a highly stable complex, as evidenced by the X-ray structure (14), insertion of the long, rod-like R-domain increases the free energy of the full-length protein and largely destabilizes the closed conformation. Moreover, our fluorescence resonance energy transfer (FRET) experiments show that while the isolated FERM domain and CTD produce a strong FRET enhancement, the value for the full-length protein corresponding to the closed conformation is significantly smaller ( Figure 4D).…”

Section: Discussionmentioning

confidence: 99%

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Insights into a Single Rod-like Helix in Activated Radixin Required for Membrane−Cytoskeletal Cross-Linking

et al. 2003

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The members of the ezrin-radixin-moesin (ERM) family of proteins function as membranecytoskeletal cross-linkers in actin-rich cell surface structures. ERM proteins are thereby thought to be essential for cortical cytoskeleton organization, cell motility, adhesion, and proliferation. These modular polypeptides consist of a central helix-rich region, termed the R-domain, that connects an N-terminal FERM domain required for membrane binding and a C-terminal region which contains a major actinbinding motif. Conformational regulation of ERM protein function occurs by association of the FERM and C-terminal domains, whereby the membrane-and actin-binding activities are mutually suppressed and the protein is thought to take an inactive "closed" form. Here we report in Vitro and in ViVo studies of radixin to address the role of the R-domain in conformational activation of ERM proteins. Remarkably, an isolated R-domain comprised of radixin 311-469 forms a monomeric, stable helical rod that spans 240 Å in length from the N-terminus to the C-terminus, most likely stabilized by extensive salt bridge interactions. By fusing green fluorescent protein variants to the FERM and C-terminal domains, we probed in Vitro conformational changes impacted by the presence of the R-domain using fluorescence resonance energy transfer (FRET). Furthermore, deletion of this unusually long R-helical structure (radixin residues 314-411) prevents ERM membrane targeting in ViVo.

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Section: Structuralsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Insights into a Single Rod-like Helix in Activated Radixin Required for Membrane−Cytoskeletal Cross-Linking

et al. 2003

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“…Canonical ERM proteins are maintained in a dormant state by an intramolecular association between the FERM domain and the C-terminal tail [38][39][40]. In response to upstream activation of Rho, Rho kinase phosphorylates a threonine residue in the C-terminal domain of ERM proteins, disrupting the head-to-tail association that maintains the closed conformation (Fig 1B).…”

Section: Merlin Structure and Modificationsmentioning

confidence: 99%

Merlin: a tumour suppressor with functions at the cell cortex and in the nucleus

et al. 2012

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Inhibition of proliferation by cell-to-cell contact is essential for tissue organization, and its disruption contributes to tumorigenesis. The FERM domain protein Merlin, encoded by the NF2 tumour suppressor gene, is an important mediator of contact inhibition. Merlin was thought to inhibit mitogenic signalling and activate the Hippo pathway by interacting with diverse target-effectors at or near the plasma membrane. However, recent studies highlight that Merlin pleiotropically affects signalling by migrating into the nucleus and inducing a growth-suppressive programme of gene expression through its direct inhibition of the CRL4 DCAF1 E3 ubiquitin ligase. In addition, Merlin promotes the establishment of epithelial adhesion and polarity by recruiting Par3 and aPKC to E-cadherin-dependent junctions, and by ensuring the assembly of tight junctions. These recent advances suggest that Merlin acts at the cell cortex and in the nucleus in a similar, albeit antithetic, manner to the oncogene β-catenin.

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“…Conformational changes may also take place in the FERM domain, which is directly affected by membrane binding. However, comparison of crystallographic data on the FERM domain in the absence [83] or presence of the C-terminal domain [84] or of IP 3 [15] showed essentially the same organization of the 3 subdomains, with important displacements observed locally, but with no obvious loss of secondary structure elements [83,84]. Thus, in light of the available crystallographic data, modifications in the secondary structure content arise from alterations in the C-terminal domain.…”

Section: Conformational Changes Of Erm Upon Pip 2 Bindingmentioning

confidence: 88%

Model membranes to shed light on the biochemical and physical properties of ezrin/radixin/moesin

2013

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Ezrin, radixin and moesin (ERM) proteins are now more and more recognized to play a key role in a large number of important physiological processes such as morphogenesis, cancer metastasis and virus infection. Several recent reviews extensively discuss their biological functions [1][2][3][4]. In this review, we will first remind the main features of this family of proteins, which are now known as linkers and regulators of the plasma membrane/cytoskeleton linkage. We will then briefly review their implication in pathological processes such as cancer and viral infection. In a second part, we will focus on biochemical and biophysical approaches to study ERM interaction with lipid membranes and conformational change in well-defined environments. In vitro studies using biomimetic lipid membranes, especially large unilamellar vesicles (LUVs), giant unilamellar vesicles (GUVs) and supported lipid bilayers (SLBs) and recombinant proteins help to understand the molecular mechanism of conformational activation of ERM proteins. These tools are aimed to decorticate the different steps of the interaction, to simplify the experiments performed in vivo in much more complex biological environments. KeywordsEzrin; radixin and moesin; biomimetic membranes; phosphoinositol (4,5)-bisphosphate (PIP 2 ); large unilamellar vesicles; supported lipid bilayers; giant unilamelar vesicles Corresponding author: Catherine Picart, CNRS UMR 5628 (LMGP), Grenoble Institute of Technology and CNRS, 3 parvis Louis Néel, F-38016 Grenoble Cedex, France. Europe PMC Funders GroupAuthor Manuscript Biochimie. Author manuscript; available in PMC 2014 July 28. Published in final edited form as:Biochimie. 2013 January ; 95(1): 3-11. doi:10.1016/j.biochi.2012.09.033. Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts Biological importance of Ezrin, Radixin and Moesin General overview of ERM proteins (Ezrin, Radixin, Moesin)ERM proteins are localized at the plasma membrane in actin-rich surface structures (Fig 1) [5], such as microvilli, membrane ruffles, and lamellipodia in gut cells, lymphocytes, hepatocytes, spermatozoids, fibroblasts and in a variety of other cell types [5][6][7][8][9]. They are involved in various physiological processes including establishment of cell polarity, cell motility and cell signaling [10]. They act as linkers between the plasma membrane and the cortical actin cytoskeleton. From a structural point of view, ERMs are constituted of 3 domains : a membrane binding domain, also known as FERM (for band 4.1 protein, ezrin, radixin and moesin), and intermediary region and a actin binding domain called C-ERMAD (for C-terminal ERM-association domain) (Fig 2A).The FERM domain, constituted of ~300 amino acids, is characteristic of the proteins of the band 4.1 superfamily. These proteins also present other types of domains, including PDZ, tyrosine phosphatase, SH2-like, tyrosine kinase, kinase-like, myosin head, and PH domains [11]. In ERM proteins, the FERM domain is followed by a long α-helical region, whi...

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Structure of the ERM Protein Moesin Reveals the FERM Domain Fold Masked by an Extended Actin Binding Tail Domain

Cited by 562 publications

References 66 publications

Insights into a Single Rod-like Helix in Activated Radixin Required for Membrane−Cytoskeletal Cross-Linking

Insights into a Single Rod-like Helix in Activated Radixin Required for Membrane−Cytoskeletal Cross-Linking

Merlin: a tumour suppressor with functions at the cell cortex and in the nucleus

Model membranes to shed light on the biochemical and physical properties of ezrin/radixin/moesin

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