TFF1 is a protective peptide of the Trefoil Factor Family (TFF), which is co-secreted with the mucin MUC5AC, gastrokine 2 (GKN2), and IgG Fc binding protein (FCGBP) from gastric surface mucous cells. Tff1-deficient mice obligatorily develop antropyloric adenoma and about 30% progress to carcinomas, indicating that Tff1 is a tumor suppressor. As a hallmark, TFF1 contains seven cysteine residues with three disulfide bonds stabilizing the conserved TFF domain. Here, we systematically investigated the molecular forms of TFF1 in the human gastric mucosa. TFF1 mainly occurs in an unusual monomeric form, but also as a homodimer. Furthermore, minor amounts of TFF1 form heterodimers with GKN2, FCGBP, and an unknown partner protein, respectively. TFF1 also binds to the mucin MUC6 in vitro, as shown by overlay assays with synthetic 125I-labeled TFF1 homodimer. The dominant presence of a monomeric form with a free thiol group at Cys-58 is in agreement with previous studies in Xenopus laevis and mouse. Cys-58 is likely highly reactive due to flanking acid residues (PPEEEC58EF) and might act as a scavenger for extracellular reactive oxygen/nitrogen species protecting the gastric mucosa from damage by oxidative stress, e.g., H2O2 generated by dual oxidase (DUOX).
The three trefoil factor family peptides (TFF1, TFF2, TFF3) with their lectin activities play important roles in mucosal protection and repair. Major gaps in understanding their molecular function have however hampered therapeutic development for gastrointestinal disorders. Here, we provide a critical overview of the status quo.
Voltage-gated
sodium (Na
V
) channels are pore-forming
transmembrane proteins that play essential roles in excitable cells,
and they are key targets for antiepileptic, antiarrhythmic, and analgesic
drugs. We implemented a heterobivalent design strategy to modulate
the potency, selectivity, and binding kinetics of Na
V
channel
ligands. We conjugated μ-conotoxin KIIIA, which occludes the
pore of the Na
V
channels, to an analogue of huwentoxin-IV,
a spider-venom peptide that allosterically modulates channel gating.
Bioorthogonal hydrazide and copper-assisted azide–alkyne cycloaddition
conjugation chemistries were employed to generate heterobivalent ligands
using polyethylene glycol linkers spanning 40–120 Å. The
ligand with an 80 Å linker had the most pronounced bivalent effects,
with a significantly slower dissociation rate and 4–24-fold
higher potency compared to those of the monovalent peptides for the
human Na
V
1.4 channel. This study highlights the power of
heterobivalent ligand design and expands the repertoire of pharmacological
probes for exploring the function of Na
V
channels.
α-Conotoxins are competitive antagonists of nicotinic acetylcholine receptors (nAChRs). Their high selectivity and affinity for the various subtypes of nAChRs have led to significant advances in our understanding of the structure and function of these key ion channels. Here we report the discovery of a novel 4/7 α-conotoxin, MrIC from the venom duct of Conus marmoreus, which acts as an agonist at the endogenous human α7 nAChR in SH-SY5Y cells pretreated with PNU120596 (PNU). This unique agonist activity of MrIC at α7 nAChRs may guide the development of novel α7 nAChR modulators.
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