ERM protein family

Available protein structures:
Pfam	structures / ECOD
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary
PDB	1ef1 , 1e5w , 1sgh

Ezrin/radixin/moesin family
Ezrin/radixin/moesin family
	Crystallographic structure of the N-terminal domain of moesin.
Identifiers
Symbol	ERM
Pfam	PF00769
InterPro	IPR011259
SCOP2	1ef1 / SCOPe / SUPFAM
Pfam
Available protein structures:
Pfam	structures / ECOD
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary
PDB	1ef1 , 1e5w , 1sgh

Last updated February 04, 2024

The ERM protein family consists of three closely related proteins, ezrin,^[2] radixin ^[3] and moesin.^[4]^[5] The three paralogs, ezrin, radixin and moesin, are present in vertebrates, whereas other species have only one ERM gene. Therefore, in vertebrates these paralogs likely arose by gene duplication.^[6]

Structure

ERM molecules contain the following three domains:^[5]

N-terminal globular domain, also called FERM domain (Band 4.1, ezrin, radixin, moesin). The FERM domain allows ERM proteins to interact with integral proteins of the plasma membrane, or scaffolding proteins localized beneath the plasma membrane.^[6] The FERM domain is composed of three subdomains (F1, F2, F3) that are arranged as a cloverleaf.
extended alpha-helical domain.
charged C-terminal domain. This domain mediates the interaction with F-actin.

Ezrin, radixin and moesin also contain a polyproline region between the central helical and C-terminal domains.

Function

ERM proteins crosslink actin filaments with plasma membranes. They co-localize with CD44 at actin filament-plasma membrane interaction sites, associating with CD44 via their N-terminal domains and with actin filaments via their C-terminal domains.^[5]^[8]

The ERM protein moesin directly binds to microtubules via its N-terminal FERM domain in vitro and stabilizes microtubules at the cell cortex in vivo. This interaction is required for specific ERM-dependent functions in mitosis.^[9]

Activation

ERM proteins are highly regulated proteins. They exist in two forms:^[6]^[7]

the FERM domain is able to interact with the F-actin binding site and this head-to-tail interaction maintains ERM proteins into a folded form; in this state, ERM proteins are inactive for the folding prevents either integral protein binding, or actin-binding.
if this head-to-tail interaction is disrupted, ERM proteins unfold, leading to an open and active conformation.

In culture cells, ERM proteins mainly exhibit the folded conformation (about 80-85%^[10]).

The current model for ERM protein activation is a two-step mechanism:^[11]

First, phosphatidylinositol 4,5-bisphosphate interaction at the plasma membrane induces a pre-opening of the ERM molecule.
Then, a not yet identified kinase phosphorylates a threonine localized in a highly conserved region of the C-terminal domain. The phosphate will stabilize the opening of the molecule.

Related Research Articles

In mammalian cells, vinculin is a membrane-cytoskeletal protein in focal adhesion plaques that is involved in linkage of integrin adhesion molecules to the actin cytoskeleton. Vinculin is a cytoskeletal protein associated with cell-cell and cell-matrix junctions, where it is thought to function as one of several interacting proteins involved in anchoring F-actin to the membrane.

Merlin is a cytoskeletal protein. In humans, it is a tumor suppressor protein involved in neurofibromatosis type II. Sequence data reveal its similarity to the ERM protein family.

Cortactin is a monomeric protein located in the cytoplasm of cells that can be activated by external stimuli to promote polymerization and rearrangement of the actin cytoskeleton, especially the actin cortex around the cellular periphery. It is present in all cell types. When activated, it will recruit Arp2/3 complex proteins to existing actin microfilaments, facilitating and stabilizing nucleation sites for actin branching. Cortactin is important in promoting lamellipodia formation, invadopodia formation, cell migration, and endocytosis.

Leukosialin also known as sialophorin or CD43 is a transmembrane cell surface protein that in humans is encoded by the SPN (sialophorin) gene.

Talin is a high-molecular-weight cytoskeletal protein concentrated at regions of cell–substratum contact and, in lymphocytes, at cell–cell contacts. Discovered in 1983 by Keith Burridge and colleagues, talin is a ubiquitous cytosolic protein that is found in high concentrations in focal adhesions. It is capable of linking integrins to the actin cytoskeleton either directly or indirectly by interacting with vinculin and α-actinin.

Ezrin also known as cytovillin or villin-2 is a protein that in humans is encoded by the EZR gene.

Zonula occludens-1 ZO-1, also known as Tight junction protein-1 is a 220-kD peripheral membrane protein that is encoded by the TJP1 gene in humans. It belongs to the family of zonula occludens proteins, which are tight junction-associated proteins and of which, ZO-1 is the first to be cloned. It was first isolated in 1986 by Stevenson and Goodenough using a monoclonal antibody raised in rodent liver to recognise a 225-kD polypeptide in whole liver homogenates and in tight junction-enriched membrane fractions. It has a role as a scaffold protein which cross-links and anchors Tight Junction (TJ) strand proteins, which are fibril-like structures within the lipid bilayer, to the actin cytoskeleton.

Sodium-hydrogen antiporter 3 regulator 1 is a regulator of Sodium-hydrogen antiporter 3. It is encoded by the gene SLC9A3R1. It is also known as ERM Binding Protein 50 (EBP50) or Na+/H+ Exchanger Regulatory Factor (NHERF1). It is believed to interact via long-range allostery, involving significant protein dynamics.

Intercellular adhesion molecule 2 (ICAM2), also known as CD102, is a human gene, and the protein resulting from it.

Sodium-hydrogen exchange regulatory cofactor NHE-RF2 (NHERF-2) also known as tyrosine kinase activator protein 1 (TKA-1) or SRY-interacting protein 1 (SIP-1) is a protein that in humans is encoded by the SLC9A3R2 gene.

Moesin is a protein that in humans is encoded by the MSN gene.

Vasodilator-stimulated phosphoprotein is a protein that in humans is encoded by the VASP gene.

Radixin is a protein that in humans is encoded by the RDX gene.

Zyxin is a protein that in humans is encoded by the ZYX gene.

Microtubule-actin cross-linking factor 1, isoforms 1/2/3/5 is a protein that in humans is encoded by the MACF1 gene.

Myosin X, also known as MYO10, is a protein that in humans is encoded by the MYO10 gene.

Myosin regulatory light chain interacting protein, also known as MYLIP, is a protein that in humans is encoded by the MYLIP gene.

αE-catenin, also known as Catenin alpha-1 is a protein that in humans is encoded by the CTNNA1 gene. αE-catenin is highly expressed in cardiac muscle and localizes to adherens junctions at intercalated disc structures where it functions to mediate the anchorage of actin filaments to the sarcolemma. αE-catenin also plays a role in tumor metastasis and skin cell function.

Talin-1 is a protein that in humans is encoded by the TLN1 gene. Talin-1 is ubiquitously expressed, and is localized to costamere structures in cardiac and skeletal muscle cells, and to focal adhesions in smooth muscle and non-muscle cells. Talin-1 functions to mediate cell-cell adhesion via the linkage of integrins to the actin cytoskeleton and in the activation of integrins. Altered expression of talin-1 has been observed in patients with heart failure, however no mutations in TLN1 have been linked with specific diseases.

In molecular biology, the FERM domain is a widespread protein module involved in localising proteins to the plasma membrane. FERM domains are found in a number of cytoskeletal-associated proteins that associate with various proteins at the interface between the plasma membrane and the cytoskeleton. The FERM domain is located at the N terminus in the majority of proteins in which it is found.

References

↑ PDB: 1E5W ; Edwards SD, Keep NH (June 2001). "The 2.7 Å crystal structure of the activated FERM domain of moesin: an analysis of structural changes on activation". Biochemistry. 40 (24): 7061–8. doi:10.1021/bi010419h. PMID 11401550.
↑ Bretscher A (August 1983). "Purification of an 80,000-dalton protein that is a component of the isolated microvillus cytoskeleton, and its localization in nonmuscle cells". J. Cell Biol. 97 (2): 425–32. doi:10.1083/jcb.97.2.425. PMC 2112519 . PMID 6885906.
↑ Tsukita S, Hieda Y, Tsukita S (June 1989). "A new 82-kD barbed end-capping protein (radixin) localized in the cell- to-cell adherens junction: purification and characterization". J. Cell Biol. 108 (6): 2369–82. doi:10.1083/jcb.108.6.2369. PMC 2115614 . PMID 2500445.
↑ Lankes W, Griesmacher A, Grünwald J, Schwartz-Albiez R, Keller R (May 1988). "A heparin-binding protein involved in inhibition of smooth-muscle cell proliferation". Biochem. J. 251 (3): 831–42. doi:10.1042/bj2510831. PMC 1149078 . PMID 3046603.
1 2 3 Tsukita S, Yonemura S, Tsukita S (February 1997). "ERM proteins: head-to-tail regulation of actin-plasma membrane interaction". Trends Biochem. Sci. 22 (2): 53–8. doi:10.1016/S0968-0004(96)10071-2. PMID 9048483.
1 2 3 Bretscher A, Edwards K, Fehon RG (August 2002). "ERM proteins and merlin: integrators at the cell cortex". Nat Rev Mol Cell Biol. 3 (8): 586–99. doi:10.1038/nrm882. PMID 12154370. S2CID 26970178.
1 2 Fiévet B, Louvard D, Arpin M (May 2007). "ERM proteins in epithelial cell organization and functions". Biochim Biophys Acta. 1773 (5): 653–60. doi: 10.1016/j.bbamcr.2006.06.013 . PMID 16904765.
↑ Yonemura S, Hirao M, Doi Y, Takahashi N, Kondo T, Tsukita S, Tsukita S (February 1998). "Ezrin/Radixin/Moesin (ERM) Proteins Bind to a Positively Charged Amino Acid Cluster in the Juxta-Membrane Cytoplasmic Domain of CD44, CD43, and ICAM-2". J. Cell Biol. 140 (4): 885–95. doi:10.1083/jcb.140.4.885. PMC 2141743 . PMID 9472040.
↑ Solinet S, Mahmud K, Stewman SF, Ben El Kadhi K, Decelle B, Talje L, Ma A, Kwok BH, Carreno S (July 2013). "The actin-binding ERM protein Moesin binds to and stabilizes microtubules at the cell cortex". J. Cell Biol. 202 (2): 251–60. doi:10.1083/jcb.201304052. PMC 3718980 . PMID 23857773.
↑ Gautreau A, Louvard D, Arpin M (July 2000). "Morphogenic Effects of Ezrin Require a Phosphorylation-Induced Transition from Oligomers to Monomers at the Plasma Membrane". J. Cell Biol. 150 (1): 193–203. doi:10.1083/jcb.150.1.193. PMC 2185562 . PMID 10893267.
↑ Fievet BT, Gautreau A, Roy C, Del Maestro L, Mangeat P, Louvard D, Arpin M (March 2004). "Phosphoinositide binding and phosphorylation act sequentially in the activation mechanism of ezrin". J. Cell Biol. 164 (5): 653–9. doi:10.1083/jcb.200307032. PMC 2172172 . PMID 14993232.

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[pmid11401550-1] PDB: 1E5W ; Edwards SD, Keep NH (June 2001). "The 2.7 Å crystal structure of the activated FERM domain of moesin: an analysis of structural changes on activation". Biochemistry. 40 (24): 7061–8. doi:10.1021/bi010419h. PMID 11401550.

[pmid6885906-2] Bretscher A (August 1983). "Purification of an 80,000-dalton protein that is a component of the isolated microvillus cytoskeleton, and its localization in nonmuscle cells". J. Cell Biol. 97 (2): 425–32. doi:10.1083/jcb.97.2.425. PMC 2112519 . PMID 6885906.

[pmid2500445-3] Tsukita S, Hieda Y, Tsukita S (June 1989). "A new 82-kD barbed end-capping protein (radixin) localized in the cell- to-cell adherens junction: purification and characterization". J. Cell Biol. 108 (6): 2369–82. doi:10.1083/jcb.108.6.2369. PMC 2115614 . PMID 2500445.

[pmid3046603-4] Lankes W, Griesmacher A, Grünwald J, Schwartz-Albiez R, Keller R (May 1988). "A heparin-binding protein involved in inhibition of smooth-muscle cell proliferation". Biochem. J. 251 (3): 831–42. doi:10.1042/bj2510831. PMC 1149078 . PMID 3046603.

[pmid9048483-5] 1 2 3 Tsukita S, Yonemura S, Tsukita S (February 1997). "ERM proteins: head-to-tail regulation of actin-plasma membrane interaction". Trends Biochem. Sci. 22 (2): 53–8. doi:10.1016/S0968-0004(96)10071-2. PMID 9048483.

[pmid12154370-6] 1 2 3 Bretscher A, Edwards K, Fehon RG (August 2002). "ERM proteins and merlin: integrators at the cell cortex". Nat Rev Mol Cell Biol. 3 (8): 586–99. doi:10.1038/nrm882. PMID 12154370. S2CID 26970178.

[pmid16904765-7] 1 2 Fiévet B, Louvard D, Arpin M (May 2007). "ERM proteins in epithelial cell organization and functions". Biochim Biophys Acta. 1773 (5): 653–60. doi: 10.1016/j.bbamcr.2006.06.013 . PMID 16904765.

[pmid9472040-8] Yonemura S, Hirao M, Doi Y, Takahashi N, Kondo T, Tsukita S, Tsukita S (February 1998). "Ezrin/Radixin/Moesin (ERM) Proteins Bind to a Positively Charged Amino Acid Cluster in the Juxta-Membrane Cytoplasmic Domain of CD44, CD43, and ICAM-2". J. Cell Biol. 140 (4): 885–95. doi:10.1083/jcb.140.4.885. PMC 2141743 . PMID 9472040.

[pmid23857773-9] Solinet S, Mahmud K, Stewman SF, Ben El Kadhi K, Decelle B, Talje L, Ma A, Kwok BH, Carreno S (July 2013). "The actin-binding ERM protein Moesin binds to and stabilizes microtubules at the cell cortex". J. Cell Biol. 202 (2): 251–60. doi:10.1083/jcb.201304052. PMC 3718980 . PMID 23857773.

[pmid10893267-10] Gautreau A, Louvard D, Arpin M (July 2000). "Morphogenic Effects of Ezrin Require a Phosphorylation-Induced Transition from Oligomers to Monomers at the Plasma Membrane". J. Cell Biol. 150 (1): 193–203. doi:10.1083/jcb.150.1.193. PMC 2185562 . PMID 10893267.

[pmid14993232-11] Fievet BT, Gautreau A, Roy C, Del Maestro L, Mangeat P, Louvard D, Arpin M (March 2004). "Phosphoinositide binding and phosphorylation act sequentially in the activation mechanism of ezrin". J. Cell Biol. 164 (5): 653–9. doi:10.1083/jcb.200307032. PMC 2172172 . PMID 14993232.

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