{PDOC50024}
{PS50024; SEA}
{BEGIN}
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* SEA domain profile *
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The  SEA  domain has been named after the first three proteins in which it was
identified (Sperm    protein,  Enterokinase and Agrin). SEA domains consist of
about 120  residues,  of which about 80 residues are highly conserved. The SEA
domains always  exist in the extracellular region and often are accompanied by
an-O-linked glycochain  at the N-terminal side. The SEA domain is found in one
or  more  copies  in mosaic extracellular or transmembrane proteins [1,2,3]. A
subclass of proteins with the SEA domain fold exists as heterodimers generated
by autoproteolytic cleavage between a serine and a glycine at a characteristic
GSVVV sequence. The result is a heterodimerix yet single-domain structure. For
the SEA  domains,  this  cleavage  reaction  may  have  evolved  as a membrane
protective function and/or to serve as a receptor-ligand entity. It seems that
the GSVVV-containing   SEA   domains   have   evolved   to  enable  their  own
dissociation, whereas  SEA domains without the proteolytic sequence and with a
conserved disulfid have evolved to be stable [4,5].

The SEA  domain  forms  a  unique  alpha/beta  sandwich fold, with the N and C
termini on  the  same  side  of  the molecule (see <PDB:1IVZ>). The alpha/beta
sandwich fold  can  be  divided  into  two layers. One layer consists of four-
stranded antiparallel  beta  sheets and a short alpha helix, whereas the other
layer consists  of  two  long alpha helices and two-stranded short beta sheets
[5,6].

Some proteins known to contain a SEA domain are listed below:

 - Vertebrate  agrin,  an  heparan sulfate proteoglycan of the basal lamina of
   the neuromuscular  junction.  It  is  responsible  for  the  clustering  of
   acetylcholine receptors  (AChRs)  and  other  proteins at the neuromuscular
   junction.
 - Mammalian  enterokinase.  It  catalyzes  the  conversion  of trypsinogen to
   trypsin which    in    turn    activates    other    proenzymes   including
   chymotrypsinogen, procarboxypeptidases, and proelastases.
 - 63  kDa  sea  urchin  sperm  protein  (SP63). It might mediate sperm-egg or
   sperm-matrix interactions.
 - Animal  perlecan,  a  heparan  sulfate containing proteoglycan found in all
   basement membranes.  It  interacts  with other basement membrane components
   such as  laminin and collagen type IV and serves as an attachment substrate
   for cells.
 - Some  vertebrate epithelial mucins. They form a family of secreted and cell
   surface glycoproteins  expressed  by  epithelial  tissues and implicated in
   epithelial cell protection, adhesion modulation and signaling.
 - Mammalian  cell  surface antigen 114/A10, an integral transmembrane protein
   that is  highly  expressed  in  hematopoietic  progenitor  cells  and IL-3-
   dependent cell lines.

The profile we have developed covers the entire SEA domain, e.g. the conserved
region and the less conserved extension following it.

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

-Last update: December 2013 / Profile and text revised.

[ 1] Bork P., Patthy L.
     "The SEA module: a new extracellular domain associated with
     O-glycosylation."
     Protein Sci. 4:1421-1425(1995).
     PubMed=7670383
[ 2] Sasaki T., Costell M., Mann K., Timpl R.
     "Inhibition of glycosaminoglycan modification of perlecan domain I by
     site-directed mutagenesis changes protease sensitivity and laminin-1
     binding activity."
     FEBS Lett. 435:169-172(1998).
     PubMed=9762901
[ 3] Costell M., Mann K., Yamada Y., Timpl R.
     "Characterization of recombinant perlecan domain I and its
     substitution by glycosaminoglycans and oligosaccharides."
     Eur. J. Biochem. 243:115-121(1997).
     PubMed=9030729
[ 4] Johansson D.G., Macao B., Sandberg A., Haerd T.
     "SEA domain autoproteolysis accelerated by conformational strain:
     mechanistic aspects."
     J. Mol. Biol. 377:1130-1143(2008).
     PubMed=18314133; DOI=10.1016/j.jmb.2008.01.050
[ 5] Macao B., Johansson D.G., Hansson G.C., Hard T.
     "Autoproteolysis coupled to protein folding in the SEA domain of the
     membrane-bound MUC1 mucin."
     Nat. Struct. Mol. Biol. 13:71-76(2006).
     PubMed=16369486; DOI=10.1038/nsmb1035
[ 6] Maeda T., Inoue M., Koshiba S., Yabuki T., Aoki M., Nunokawa E.,
     Seki E., Matsuda T., Motoda Y., Kobayashi A., Hiroyasu F.,
     Shirouzu M., Terada T., Hayami N., Ishizuka Y., Shinya N.,
     Tatsuguchi A., Yoshida M., Hirota H., Matsuo Y., Tani K., Arakawa T.,
     Carninci P., Kawai J., Hayashizaki Y., Kigawa T., Yokoyama S.
     "Solution structure of the SEA domain from the murine homologue of
     ovarian cancer  antigen CA125 (MUC16)."
     J. Biol. Chem. 279:13174-13182(2004).
     PubMed=14764598; DOI=10.1074/jbc.M309417200

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