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>) .
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 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
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
Intestinal sucrase-isomaltase (EC 188.8.131.52 / EC 184.108.40.206), a vertebrate
membrane-bound, multifunctional enzyme complex which hydrolyzes sucrose,
maltose and isomaltose (see <PDOC00120>).
Lysosomal α-glucosidase (EC 220.127.116.11) (acid maltase), a vertebrate
extracellular glycosidase (see <PDOC00120>).
Structurally the P-type domain can be represented as shown below.
Lemercinier X. Muskett F.W. Cheeseman B. McIntosh P.B. Thim L. Carr M.D.
High-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.
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