A cysteine-rich domain of approximately forty five amino-acid residues has been found in some extracellular eukaryotic proteins [ (PUBMED:7820556) (PUBMED:9187350) (PUBMED:8518738) (PUBMED:8267796) ]. It is known as either the 'P', 'trefoil' or 'TFF' domain, and contains six cysteines linked by three disulphide bonds with connectivity 1-5, 2-4, 3-6. 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 beta-sheet, which is capped by an irregular loop and forms a central hairpin (loop 3). The beta-sheet is preceded by a short alpha-helix, with majority of the remainder of the domain contained in two loops, which lie on either side of the central hairpin.
protein pS2 (TFF1), a protein secreted by the stomach mucosa
spasmolytic polypeptide (SP) (TFF2), a protein of about 115 residues that inhibits gastrointestinal motility and gastric acid secretion
intestinal trefoil factor (ITF) (TFF3)
Xenopus laevis stomach proteins xP1 and xP4
xenopus integumentary mucins A.1 (FIM-A.1 or preprospasmolysin) and C.1 (FIM-C.1), proteins which may be involved in defence against microbial infections by protecting the epithelia from the external environment
xenopus skin protein xp2 (or APEG)
Zona pellucida sperm-binding protein B (ZP-B)
intestinal sucrase-isomaltase ( EC 3.2.1.48 / EC 3.2.1.10 ), a vertebrate membrane bound, multifunctional enzyme complex which hydrolyses sucrose, maltose and isomaltose
The unique three-loop structure of the trefoil motif, formed by intrachain disulfide bonds in a 1-5, 2-4, 3-6 configuration between six conserved cysteine residues, is the defining feature of a recently recognized family of peptides. Expression of trefoil peptides is closely related to that of mucin glycoproteins in diverse biological sources. Three distinct members of the family (pS2, intestinal trefoil factor, and spasmolytic polypeptide) are produced in the mammalian gastrointestinal tract by mucus-secreting cells and targeted primarily for luminal secretion. The compact structure of the trefoil motif may be responsible for marked resistance of trefoil peptides to proteolytic digestion, enabling them to function in the harsh environment of the gastrointestinal lumen. Trefoil peptides are ectopically expressed adjacent to areas of inflammation within the gastrointestinal tract and may play an important role in both maintaining the barrier function of mucosal surfaces and facilitating healing after injury.
Solution structure of a trefoil-motif-containing cell growth factor, porcine spasmolytic protein.
Proc Natl Acad Sci U S A. 1994; 91: 2206-10
Display abstract
The porcine spasmolytic protein (pSP) is a 106-residue cell growth factor that typifies a family of eukaryotic proteins that contain at least one copy of an approximately 40-amino acid protein domain known as the trefoil motif. In fact, pSP contains two highly homologous trefoil domains. We have determined the complete three-dimensional solution structure of pSP by using a combination of two- and three-dimensional 1H NMR spectroscopy and distance geometry calculations. pSP is a relatively elongated molecule, consisting of two compact globular domains joined via a small interface. The protein's two trefoil domains adopt the same tertiary structure and contain a core C-terminal two-stranded antiparallel beta-sheet, preceded by a 6-residue helix that packs against the N-terminal beta-strand. The remainder of the protein backbone is taken up by two short loops that lie on either side of the beta-hairpin and are linked by an extended region that wraps around the C-terminal beta-strand. The topology of the protein backbone observed for the trefoil domains in pSP represents an unusual polypeptide fold. A striking feature of both trefoil domains is a surface patch formed from five conserved residues that have no obvious structural role. The two patches are located at the far ends of the protein molecule, and we propose that these residues form at least part of the receptor binding site, or sites, on pSP.
Crystal structure of a disulfide-linked "trefoil" motif found in a large family of putative growth factors.
Proc Natl Acad Sci U S A. 1994; 91: 1084-8
Display abstract
Porcine pancreatic spasmolytic polypeptide (PSP) belongs to a large family of homologous growth factor-like polypeptides characterized by a disulfide-linked "trefoil motif," duplicated and conserved in various family members. PSP contains two trefoil motifs, has several pharmacological actions on the gut, and has growth factor properties on epithelial cells in vitro. The human PSP analogue, human spasmolytic polypeptide, appears to be involved in many regenerative situations and, especially, in healing gastrointestinal ulcers. One member of the trefoil family, pS2, is secreted in approximately 50% of estrogen-dependent human breast carcinomas, which has led to its use as a tumor prognostic marker. Both pS2 and human spasmolytic polypeptide are also widely expressed in chronic gastrointestinal ulcerative conditions such as Crohn disease. Here we report the three-dimensional structure at 2.6-A resolution of a trefoil-containing protein, namely PSP, purified from porcine pancreas. The structure shows two homologous domains that share a supersecondary structure and disulfide bond pattern. The two domains pack asymmetrically giving rise to a number of protruding loops, exposed clefts, and an unusual electrostatic surface potential. Knowledge of the structure of PSP should allow the design of mutants to investigate further the function of PSP and other trefoil-containing peptides.
The P-domain or trefoil motif: a role in renewal and pathology of mucous epithelia?
Trends Biochem Sci. 1993; 18: 239-43
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By analogy with epidermal growth factor and EGF-like repeats, the P-domain, or trefoil motif, is a characteristic shuffled module containing six invariant cysteine residues that forms the basic unit for a family of mucin-associated peptides. These P-domain peptides are potential modulators of cell growth and they are also expressed under certain pathological conditions. Furthermore, P-domains have been found as components of extracellular mosaic proteins including certain mucins, where they are thought to play a role either in protein-protein or in lectin-like interactions.
Metabolism (metabolic pathways involving proteins which contain this domain)
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This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with PD domain which could be assigned to a KEGG orthologous group, and not all proteins containing PD domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.
