{PDOC50031}
{PS50031; EH}
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* EH domain profile *
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The EH  (for Eps15 Homology) domain is a protein-protein interaction module of
approximately 95  residues  which  was  originally  identified  as  a repeated
sequence present  in  three  copies  at  the N-terminus of the tyrosine kinase
substrates Eps15  and  Eps15R  [1].  The  EH  domain was subsequently found in
several proteins  implicated  in  endocytosis,  vesicle  transport  and signal
transduction in  organisms  ranging  from  yeast  to  mammals.  EH domains are
present in one to three copies and they may include calcium-binding domains of
the EF-hand type (see <PDOC00018>) [2,3,4].

EH domains  have been shown to bind specifically but with moderate affinity to
peptide containing  short, unmodified motifs through predominantly hydrophobic
interactions. The  target  motifs  are  divided  into  three  classes: class I
consists of  the  concensus  Asn-Pro-Phe  (NPF) sequence; class II consists of
aromatic and  hydrophobic  di-  and  tripeptide  motifs, including the Phe-Trp
(FW), Trp-Trp  (WW),  and Ser-Trp-Gly (SWG) motifs; and class III contains the
His-(Thr/Ser)-Phe motif (HTF/HSF) [5,6].

The structure   of  several EH domains has been solved by NMR (see <PDB:1EH2>.
The fold  consists  of  two helix-loop-helix characteristic of EF-hand domains
and  the target  peptide  is  bound  in a hydrophobic pocket between two alpha
helices. Sequence  analysis  and structural data indicate that not all the EF-
hands are  capable  of  binding  calcium  because of mutations of the calcium-
liganding residues in the loop [7,8,9,10].

Some proteins known to contain an EH domain are listed below:

 - Mammalian  epidermal  growth  factor  receptor substrate 15 (Eps15) and the
   Eps15 related  (Eps15R)  protein. They bind to the alpha-adaptin subunit of
   AP-1 which plays a major role in clathrin-mediated endocytosis.
 - Vertebrate  intersectins. They colocalize with clathrin and interact with a
   variety of endocytic proteins.
 - Mammalian gamma-synergin.
 - Human Partner of RalBP1 protein (POB1).
 - Mouse RalBP1-associated Eps-homology protein (Reps1).
 - Mammalian  EH-domain  containing  protein  1.  EHD1  could  play  a role in
   receptor-mediated endocytosis.
 - Mammalian EH-domain containing proteins 2 (EHD2), 3 (EHD3) and 4 (EHD4).
 - Drosophila   dynamin   associated   proteins  DAP160-1  and  DAP160-2,  the
   homologues of intersectins.
 - Caenorhabditis elegans ehs-1.
 - Yeast  PAN1,  a  protein required for both the endocytic process and normal
   organization of the cortical actin cytoskeleton.
 - Yeast  END3, a protein required for the internalization step of endocytosis
   and for actin cytoskeleton organization.

The profile we developed covers the entire EH domain.

-Sequences known to belong to this class detected by the profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.
-Last update: May 2002 / First entry.

[ 1] Wong W.T., Schumacher C., Salcini A.E., Romano A., Castagnino P.,
     Pelicci P.G., Di Fiore P.
     "A protein-binding domain, EH, identified in the receptor tyrosine
     kinase substrate Eps15 and conserved in evolution."
     Proc. Natl. Acad. Sci. U.S.A. 92:9530-9534(1995).
     PubMed=7568168
[ 2] Di Fiore P.P., Pelicci P.G., Sorkin A.
     Trends Biochem. Sci. 22:411-413(1997).
[ 3] Mayer B.J.
     "Endocytosis: EH domains lend a hand."
     Curr. Biol. 9:R70-R73(1999).
     PubMed=10021353
[ 4] Santolini E., Salcini A.E., Kay B.K., Yamabhai M., Di Fiore P.P.
     "The EH network."
     Exp. Cell Res. 253:186-209(1999).
     PubMed=10579923; DOI=10.1006/excr.1999.4694
[ 5] Salcini A.E., Confalonieri S., Doria M., Santolini E., Tassi E.,
     Minenkova O., Cesareni G., Pelicci P.G., Di Fiore P.P.
     "Binding specificity and in vivo targets of the EH domain, a novel
     protein-protein interaction module."
     Genes Dev. 11:2239-2249(1997).
     PubMed=9303539
[ 6] Paoluzi S., Castagnoli L., Lauro I., Salcini A.E., Coda L., Fre' S.,
     Confalonieri S., Pelicci P.G., Di Fiore P.P., Cesareni G.
     "Recognition specificity of individual EH domains of mammals and
     yeast."
     EMBO J. 17:6541-6550(1998).
     PubMed=9822599; DOI=10.1093/emboj/17.22.6541
[ 7] de Beer T., Carter R.E., Lobel-Rice K.E., Sorkin A., Overduin M.
     Science 281:1357-1360(1998).
[ 8] Enmon J.L., de Beer T., Overduin M.
     "Solution structure of Eps15's third EH domain reveals coincident
     Phe-Trp and Asn-Pro-Phe binding sites."
     Biochemistry 39:4309-4319(2000).
     PubMed=10757979; DOI=10.1021/bi9927383
[ 9] Kim S., Cullis D.N., Feig L.A., Baleja J.D.
     "Solution structure of the Reps1 EH domain and characterization of its
     binding to NPF target sequences."
     Biochemistry 40:6776-6785(2001).
     PubMed=11389591; DOI=10.1021/bi002700m
[10] de Beer T., Hoofnagle A.N., Enmon J.L., Bowers R.C., Yamabhai M.,
     Kay B.K., Overduin M.
     Nat. Struct. Biol. 7:1018-1022(2000).

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