Catalytic region mimetics in Na+/H+ exchanger regulatory factor 4 suppress guanylate cyclase 2C activity to regulate enterotoxin triggered diarrhea.

ABSTRACT: Guanylate cyclase 2C (GCC) upon binding to the bacterial heat-stable enterotoxin ST, generates excessive cGMP, driving intestinal chloride and fluid secretion that manifests as diarrhea. We investigated the regulatory mechanism of GCC through its interactions with scaffolding proteins sodium-hydrogen exchanger regulatory factor (NHERF)1 to 4. PSD95, Dlg1, ZO-1 (PDZ) domain in NHERF4 inhibited GCC catalytic activity, while NHERF1-3 binary binding had no impact. NHERF4-mediated inhibition was mimicked by two synergistically acting peptides, (N4-110 [NH2-LERPRFCLL-COOH] and N4-195 [NH2-RHAHDVARAQL-COOH]), localized in close proximity within the PDZ1 domain. These peptides, which showed high sequence homology to the GCC catalytic domain, were mapped via 3-D structural modeling to the GCC dimer

SUBMITTER: Ramananda Y 

PROVIDER: S-EPMC12510010 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature