{PDOC00024} {PS00025; P_TREFOIL_1} {PS51448; P_TREFOIL_2} {BEGIN} *************************************************** * 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 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 (see ) [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 alpha 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 3.2.1.48 / EC 3.2.1.10), a vertebrate membrane-bound, multifunctional enzyme complex which hydrolyzes sucrose, maltose and isomaltose (see ). - Lysosomal alpha-glucosidase (EC 3.2.1.20) (acid maltase), a vertebrate extracellular glycosidase (see ). Structurally the P-type domain can be represented as shown below. +-------------------------+ | +--------------+| | | || xxCxxxxxx+xxCG#xxxxxxxCxxxxCC#xxxxxxxxWC#xxxxxxxx *************|******* | | | +----------------+ 'C': conserved cysteine involved in a disulfide bond. '#': large hydrophobic residue. '+': positively charged residue. '*': position of the pattern. -Consensus pattern: [KRH]-x(2)-C-x-[FYPSTV]-x(3,4)-[ST]-x(3)-C-x(4)-C-C-[FYWH] [The 4 C's are involved in disulfide bonds] -Sequences known to belong to this class detected by the pattern: ALL. -Other sequence(s) detected in Swiss-Prot: NONE. -Sequences known to belong to this class detected by the profile: ALL. -Other sequence(s) detected in Swiss-Prot: NONE. -Expert(s) to contact by email: Hoffmann W.; werner.hoffmann@medizin.uni-magdeburg.de -Last update: May 2009 / Text revised; profile added. [ 1] Hoffmann W., Hauser F. "The P-domain or trefoil motif: a role in renewal and pathology of mucous epithelia?" Trends Biochem. Sci. 18:239-243(1993). PubMed=8267796 [ 2] Otto B., Wright N. "Trefoil peptides. Coming up clover." Curr. Biol. 4:835-838(1994). PubMed=7820556 [ 3] Bork P. "A trefoil domain in the major rabbit zona pellucida protein." Protein Sci. 2:669-670(1993). PubMed=8518738 [ 4] Wright N.A., Hoffmann W., Otto W.R., Rio M.-C., Thim L. "Rolling in the clover: trefoil factor family (TFF)-domain peptides, cell migration and cancer." FEBS Lett. 408:121-123(1997). PubMed=9187350 [ 5] Sommer P., Blin N., Goett P. "Tracing the evolutionary origin of the TFF-domain, an ancient motif at mucous surfaces." Gene 236:133-136(1999). PubMed=10433974 [ 6] 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." Biochemistry 40:9552-9559(2001). 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