PROSITE documentation PDOC00024
P-type ('Trefoil') domain signature and profile


A cysteine-rich domain of approximately forty five amino-acid residues has been found in some extracellular eukaryotic proteins [1,2,3,4,5]. This domain is known as either the 'P', 'trefoil' or 'TFF' domain. It contains six cysteines that are linked by three disulfide bonds in a 1-5, 2-4, and 3-6 configuration. This leads to a characteristic three leafed structure ('trefoil'). The P-type domain is clearly composed of three looplike regions. The central core of the domain consists of a short two-stranded antiparallel β-sheet, which is capped by an irregular loop and forms a central hairpin (loop 3). The β-sheet is preceded by a short α-helix, with majority of the remainder of the domain contained in two loops, which lie on either side of the central hairpin (see <PDB:1E9T>) [6].

Proteins known to contain this domain are:

  • Protein pS2 (TFF1), a protein secreted by the stomach mucosa, whose gene is induced by estrogen. The exact function of pS2 is not known. It is a protein of about 65 residues and it contains a copy of the 'P' domain.
  • Spasmolytic polypeptide (SP) (TFF2), a protein of about 115 residues that inhibits gastrointestinal motility and gastric acid secretion. SP could be a growth factor. It contains two tandem copies of the 'P' domain.
  • Intestinal trefoil factor (ITF) (TFF3), an intestinal protein of about 60 residues which may have a role in promoting cell migration. It contains a copy of the 'P' domain.
  • Xenopus stomach proteins xP1 (one 'P' domain) and xP4 (four 'P' domains).
  • Xenopus integumentary mucins A.1 (FIM-A.1 or preprospasmolysin) and C.1 (FIM-C.1). These proteins could be involved in defense against microbial infections by protecting the epithelia from external environment. They are large proteins (400 residues for A.1; more than 660 residues for C.1 whose sequence is only partially known) that contain multiple copies of the 'P' domain interspersed with tandem repeats of threonine-rich, O-glycosylated regions.
  • Xenopus skin protein xp2 (or APEG) a protein that contains two 'P' domains and which exists in two alternative spliced forms that differ from the inclusion of a N-terminal region of 320 residues that consist of 33 tandem repeats of a G-[GE]-[AP](2,4)-A-E motif.
  • Zona pellucida sperm-binding protein B (ZP-B) (also known as ZP-X in rabbit and ZP-3 α in pig). This protein is a receptor-like glycoprotein whose extracellular region contains a 'P' domain followed by a ZP domain (see <PDOC00577>).
  • Intestinal sucrase-isomaltase (EC / EC, a vertebrate membrane-bound, multifunctional enzyme complex which hydrolyzes sucrose, maltose and isomaltose (see <PDOC00120>).
  • Lysosomal α-glucosidase (EC (acid maltase), a vertebrate extracellular glycosidase (see <PDOC00120>).

Structurally the P-type domain can be represented as shown below.

              |         +--------------+|
              |         |              ||
                     *************|*******         |
                                  |                |
'C': conserved cysteine involved in a disulfide bond.
'#': large hydrophobic residue.
'+': positively charged residue.
'*': position of the pattern.
Expert(s) to contact by email:

Hoffmann W.

Last update:

May 2009 / Text revised; profile added.


Technical section

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

P_TREFOIL_2, PS51448; P-type 'Trefoil' domain profile  (MATRIX)

P_TREFOIL_1, PS00025; P-type 'Trefoil' domain signature  (PATTERN)


1AuthorsHoffmann W. Hauser F.
TitleThe P-domain or trefoil motif: a role in renewal and pathology of mucous epithelia?
SourceTrends Biochem. Sci. 18:239-243(1993).
PubMed ID8267796

2AuthorsOtto B. Wright N.
TitleTrefoil peptides. Coming up clover.
SourceCurr. Biol. 4:835-838(1994).
PubMed ID7820556

3AuthorsBork P.
TitleA trefoil domain in the major rabbit zona pellucida protein.
SourceProtein Sci. 2:669-670(1993).
PubMed ID8518738

4AuthorsWright N.A. Hoffmann W. Otto W.R. Rio M.-C. Thim L.
TitleRolling in the clover: trefoil factor family (TFF)-domain peptides, cell migration and cancer.
SourceFEBS Lett. 408:121-123(1997).
PubMed ID9187350

5AuthorsSommer P. Blin N. Goett P.
TitleTracing the evolutionary origin of the TFF-domain, an ancient motif at mucous surfaces.
SourceGene 236:133-136(1999).
PubMed ID10433974

6AuthorsLemercinier X. Muskett F.W. Cheeseman B. McIntosh P.B. Thim L. Carr M.D.
TitleHigh-resolution solution structure of human intestinal trefoil factor and functional insights from detailed structural comparisons with the other members of the trefoil family of mammalian cell motility factors.
SourceBiochemistry 40:9552-9559(2001).
PubMed ID11583154

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