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 :
- 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
- 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
- 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
- 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 .
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.
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