Structure, Function, and Therapeutic Potential of the Trefoil Factor Family in the Gastrointestinal Tract

Abstract

Trefoil factor family peptides (TFF1, TFF2, and TFF3) are key players in protecting, maintaining, and repairing the gastrointestinal tract. Accordingly, they have the therapeutic potential to treat and prevent a variety of gastrointestinal disorders associated with mucosal damage. TFF peptides share a conserved motif, including three disulfide bonds that stabilize a well-defined three-loop-structure reminiscent of a trefoil. Although multiple functions have been described for TFF peptides, their mechanisms at the molecular level remain poorly understood. This review presents the status quo of TFF research relating to gastrointestinal disorders. Putative TFF receptors and protein partners are described and critically evaluated. The therapeutic potential of these peptides in gastrointestinal disorders where altered mucosal biology plays a crucial role in the underlying etiology is discussed. Finally, areas of investigation that require further research are addressed. Thus, this review provides a comprehensive update on TFF literature as well as guidance toward future research to better understand this peptide family and its therapeutic potential for the treatment of gastrointestinal disorders.

Figure 1

3D NMR structure and trefoil domain sequence of the three mammalian members of the trefoil factor family. (A) 3D NMR structure of TFF1, TFF2, and TFF3. TFF domains are shown in blue. N- and C-terminals and linker region in TFF2 are shown in green. Disulfide bonds are highlighted in yellow. (B) Amino acid sequences of human TFF1, porcine TFF2, and human TFF3, highlighting the trefoil domain (gray) and the disulfide bonds inside the trefoil domain, as well as the extra disulfide bond between Cys and Cys outside the domain in TFF2 (orange).

Figure 2

3D NMR structures of homodimeric TFF peptides. (A) Human TFF1 (hTFF1) homodimer (PDB: 1HI7). (B) Porcine TFF2 (pTFF2) dimer (PDB: 1PCP). (C) Human TFF3 (hTFF3) homodimer (PDB: 1PE3).

Figure 3

Trefoil domain sequence alignment highlighting nonconserved residues (red). The trefoil domains display 70% similarity with 35% fully conserved residues. [*] identical residue, [:] strongly similar properties, [.] weakly similar properties.