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{PDOC00566}
{PS00660; FERM_1}
{PS00661; FERM_2}
{PS50057; FERM_3}
{BEGIN}
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* FERM domain signatures and profile *
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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  alpha+beta  structure  with  one  long alpha-helix and a five-
stranded mixed  beta-sheet.  F2  is  an  all-alpha  structure with four longer
alpha-helices and one short helix. F3 consists of a sandwich of two orthogonal
antiparallel beta-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.

-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.

-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.

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

-Expert(s) to contact by email:
           Rees J.; 
jrees@vax.oxford.ac.uk -Last update: December 2004 / Pattern and text revised. [ 1] Rees D.J.G., Ades S.E., Singer S.J., Hynes R.O. "Sequence and domain structure of talin." Nature 347:685-689(1990). PubMed=2120593; DOI=10.1038/347685a0 [ 2] Funayama N., Nagafuchi A., Sato N., Tsukita S., Tsukita S. "Radixin is a novel member of the band 4.1 family." J. Cell Biol. 115:1039-1048(1991). PubMed=1955455 [ 3] Takeuchi K., Kawashima A., Nagafuchi A., Tsukita S. "Structural diversity of band 4.1 superfamily members." J. Cell Sci. 107:1921-1928(1994). PubMed=7983158 [ 4] 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. "The FERM domain: a unique module involved in the linkage of cytoplasmic proteins to the membrane." Trends Biochem. Sci. 23:281-282(1998). PubMed=9757824 [ 5] Pearson M.A., Reczek D., Bretscher A., Karplus P.A. "Structure of the ERM protein moesin reveals the FERM domain fold masked by an extended actin binding tail domain." Cell 101:259-270(2000). PubMed=10847681 [ 6] Girault J.-A., Labesse G., Mornon J.-P., Callebaut I. "The N-termini of FAK and JAKs contain divergent band 4.1 domains." Trends Biochem. Sci. 24:54-57(1999). PubMed=10098398 [ 7] Hamada K., Shimizu T., Matsui T., Tsukita S., Hakoshima T. "Structural basis of the membrane-targeting and unmasking mechanisms of the radixin FERM domain." EMBO J. 19:4449-4462(2000). PubMed=10970839; DOI=10.1093/emboj/19.17.4449 -------------------------------------------------------------------------------- PROSITE is copyrighted by the SIB Swiss Institute of Bioinformatics and distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND 4.0) License, see https://prosite.expasy.org/prosite_license.html -------------------------------------------------------------------------------- {END}