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FERM domains (F for 4.1 protein, E for ezrin, R for radixin and M for moesin) are widespread protein modules of ~300 amino-acids in length that are involved in localizing proteins to the plasma membrane. They 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 of the majority of FERM-containing proteins [1,2,3,4,5]. The FERM domain defines members of the band 4.1 superfamily, which includes [6]:

• Band 4.1, which links the spectrin-actin cytoskeleton of erythrocytes to the plasma membrane. Band 4.1 binds with a high affinity to glycophorin and with lower affinity to band 3 protein.
• Ezrin (cytovillin or p81), a component of the undercoat of the microvilli plasma membrane.
• Moesin, which is probably involved in binding major cytoskeletal structures to the plasma membrane.
• Radixin, which seems to play a crucial role in the binding of the barbed end of actin filaments to the plasma membrane in the undercoat of the cell- to-cell adherens junction (AJ).
• Talin, which binds with high affinity to vinculin and with low affinity to integrins. Talin is a high molecular weight (270 Kd) cytoskeletal protein concentrated in regions of cell-substratum contact and, in lymphocytes, of cell-cell contacts.
• Filopodin, a slime mold protein that binds actin and which is involved in the control of cell motility and chemotaxis.
• Merlin (or schwannomin). Defects in this protein are the cause of type 2 neurofibromatosis (NF2), a predisposition to tumors of the nervous system.
• Protein NBL4.
• Unconventional myosins X, VIIa and XV, which are mutated in congenital deafness.
• Focal-adhesion kinases (FAKs), cytoplasmic protein tyrosine kinases which are important for signalling through a class of extracellular matrix (ECM) receptors, the integrins.
• Janus tyrosine kinases (JAKs), a group of cytoplasmic tyrosine kinases that are non-covalently associated with the cytoplasmic tails of receptors for cytokines or polypeptidic hormones.
• Non-receptor tyrosine-protein kinase TYK2.
• Protein-tyrosine phosphatases PTPN3 (PTP-H1) and PTPN4 (PTP-MEG1). Structurally these two very similar enzymes are composed of a N-terminal band 4.1-like domain followed by a central segment of unknown function and a C-terminal catalytic domain (see <PDOC00323>). They could act at junctions between the membrane and the cytoskeleton.
• Protein-tyrosine phosphatases PTPN14 (PEZ or PTP36) and PTP-D1, PTP-RL10 and PTP2E. These phosphatases also consist of a N-terminal band 4.1-like domain and a C-terminal catalytic domain. The central domain seems to contain a SH3-binding domain.
• Caenorhabditis elegans protein phosphatase ptp-1.

Ezrin, moesin, and radixin are highly related proteins (ERM protein family), but the other proteins in which this domain is found do not share any region of similarity outside of the domain. ERM proteins are made of three domains, the FERM domain, a central helical domain and a C-terminal tail domain, which binds F-actin. The amino-acid sequence of the FERM domain is highly conserved among ERM proteins and is responsible for membrane association by direct binding to the cytoplasmic domain or tail of integral membrane proteins. ERM proteins are regulated by an intramolecular association of the FERM and C-terminal tail domains that masks their binding sites for other molecules. For cytoskeleton-membrane crosslinking, the dormant molecules becomes activated and the FERM domain attaches to the membrane by binding specific membrane proteins, while the last 34 residues of the tail bind actin filaments. Aside from binding to membranes, the activated FERM domain of ERM proteins can also bind the guanine nucleotide dissociation inhibitor of Rho GTPase (RhoDGI), which suggest that in addition to functioning as a crosslinker, ERM proteins may influence Rho signalling pathways. The crystal structure of the FERM domain reveals that it is composed of three structural modules (F1, F2, and F3) that together form a compact clover-shaped structure (see <PDB:1EF1>). F1 folds into an α+β structure with one long α-helix and a five-stranded mixed β-sheet. F2 is an all-α structure with four longer α-helices and one short helix. F3 consists of a sandwich of two orthogonal antiparallel β-sheets followed by a long helix [5,7].

The FERM domain has also been called the amino-terminal domain, the 30-kDa domain, 4.1N30, the membrane-cytoskeletal-linking domain, the ERM-like domain, the ezrin-like domain of the band 4.1 superfamily, the conserved N-terminal region, and the membrane attachment domain [4].

We have developed two signature patterns for this domain, one is based on the conserved positions found at the N-terminal extremity of the domain, the second is located in the C-terminal section.

Rees J.

December 2004 / Pattern and text revised.

PROSITE methods (with tools and information) covered by this documentation:

FERM_3, PS50057; FERM domain profile  (MATRIX)

Sequences known to belong to this class detected by the profile: ALL Other sequence(s) detected in Swiss-Prot: NONE.

• Domain architecture view of Swiss-Prot proteins matching PS50057 • Retrieve an alignment of Swiss-Prot true positive hits:   Clustal format, color, condensed view  / Clustal format, color  / Clustal format, plain text  / Fasta format • Retrieve the sequence logo from the alignment • Taxonomic tree view of all Swiss-Prot/TrEMBL entries matching PS50057 • Retrieve a list of all Swiss-Prot/TrEMBL entries matching PS50057 • Scan Swiss-Prot/TrEMBL entries against PS50057 • view ligand binding statistics

Matching PDB structures: 1E5W 1EF1 1GC6 1GC7 ... [ALL]

FERM_1, PS00660; FERM domain signature 1  (PATTERN)

Consensus pattern: W-[LIV]-x(3)-[KRQ]-x-[LIVM]-x(2)-[QH]-x(0,2)-[LIVMF]-x(6,8)-[LIVMF]-x(3,5)-F-[FY]-x(2)-[DENS] Sequences known to belong to this class detected by the pattern: ALL Other sequence(s) detected in Swiss-Prot: NONE.

• Retrieve an alignment of Swiss-Prot true positive hits:   Clustal format, color, condensed view  / Clustal format, color  / Clustal format, plain text  / Fasta format • Retrieve the sequence logo from the alignment • Taxonomic tree view of all Swiss-Prot/TrEMBL entries matching PS00660 • Retrieve a list of all Swiss-Prot/TrEMBL entries matching PS00660 • Scan Swiss-Prot/TrEMBL entries against PS00660 • view ligand binding statistics

Matching PDB structures: 1E5W 1EF1 1GC6 1GC7 ... [ALL]

FERM_2, PS00661; FERM domain signature 2  (PATTERN)

Consensus pattern: [HYW]-x(9)-[DENQSTV]-[SA]-x(3)-[FYC]-[LIVM]-x(2,3)-[ACVWD]-x(2)-[LM]-x(2)-[FY]-[GM]-x-[DENQSTH]-[LIVMFYS] Sequences known to belong to this class detected by the pattern: ALL Other sequence(s) detected in Swiss-Prot: NONE.

• Retrieve an alignment of Swiss-Prot true positive hits:   Clustal format, color, condensed view  / Clustal format, color  / Clustal format, plain text  / Fasta format • Retrieve the sequence logo from the alignment • Taxonomic tree view of all Swiss-Prot/TrEMBL entries matching PS00661 • Retrieve a list of all Swiss-Prot/TrEMBL entries matching PS00661 • Scan Swiss-Prot/TrEMBL entries against PS00661 • view ligand binding statistics

Matching PDB structures: 1E5W 1EF1 1GC6 1GC7 ... [ALL]

1	Authors	Rees D.J.G., Ades S.E., Singer S.J., Hynes R.O.
	Title	Sequence and domain structure of talin.
	Source	Nature 347:685-689(1990).
	PubMed ID	2120593
	DOI	10.1038/347685a0

2	Authors	Funayama N., Nagafuchi A., Sato N., Tsukita S., Tsukita S.
	Title	Radixin is a novel member of the band 4.1 family.
	Source	J. Cell Biol. 115:1039-1048(1991).
	PubMed ID	1955455

3	Authors	Takeuchi K., Kawashima A., Nagafuchi A., Tsukita S.
	Title	Structural diversity of band 4.1 superfamily members.
	Source	J. Cell Sci. 107:1921-1928(1994).
	PubMed ID	7983158

4	Authors	Chishti A.H., Kim A.C., Marfatia S.M., Lutchman M., Hanspal M., Jindal H., Liu S.-C., Low P.S., Rouleau G.A., Mohandas N., Chasis J.A., Conboy J.G., Gascard P., Takakuwa Y., Huang S.-C., Benz E.J. Jr., Bretscher A., Fehon R.G., Gusella J.F., Ramesh V., Solomon F., Marchesi V.T., Tsukita S., Tsukita S., Hoover K.B.
	Title	The FERM domain: a unique module involved in the linkage of cytoplasmic proteins to the membrane.
	Source	Trends Biochem. Sci. 23:281-282(1998).
	PubMed ID	9757824

5	Authors	Pearson M.A., Reczek D., Bretscher A., Karplus P.A.
	Title	Structure of the ERM protein moesin reveals the FERM domain fold masked by an extended actin binding tail domain.
	Source	Cell 101:259-270(2000).
	PubMed ID	10847681

6	Authors	Girault J.-A., Labesse G., Mornon J.-P., Callebaut I.
	Title	The N-termini of FAK and JAKs contain divergent band 4.1 domains.
	Source	Trends Biochem. Sci. 24:54-57(1999).
	PubMed ID	10098398

7	Authors	Hamada K., Shimizu T., Matsui T., Tsukita S., Hakoshima T.
	Title	Structural basis of the membrane-targeting and unmasking mechanisms of the radixin FERM domain.
	Source	EMBO J. 19:4449-4462(2000).
	PubMed ID	10970839
	DOI	10.1093/emboj/19.17.4449

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