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Vol. 58, Issue 5, 911-919, November 2000
Center for Basic Research in Digestive Diseases, Departments of
Internal Medicine and Biochemistry/Molecular Biology, Mayo Clinic and
Foundation, Rochester, Minnesota
The secretin receptor is prototypic of the class II family of G
protein-coupled receptors, with a long extracellular amino-terminal domain containing six highly conserved Cys residues and one Cys residue
(Cys11) that is present only in the most closely related
family members. This domain is critical for function, with some
component Cys residues believed to be involved in key disulfide bonds,
although these have never been directly demonstrated. Here, we examine the functional importance of each of these residues and determine their
involvement in disulfide bonds. Secretin binding was markedly diminished after treating cells with cell-impermeant reducing reagents,
supporting the presence of important extracellular disulfide bonds. To
determine whether the amino-terminal domain was covalently attached to
the receptor body by disulfide linkage, a strategy was implemented that
involved introduction of an acid-labile Asp-Pro sequence to enable
specific cleavage at the boundary of these domains. Under nonreducing
conditions, the amino terminus was released from the receptor body,
supporting the absence of covalent association between these domains.
Quantitative [14C]iodoacetamide incorporation into the
isolated amino-terminal domain of the receptor in the absence and
presence of chemical reduction established the ratio of free to total
Cys residues as 1:7, consistent with three disulfide bonds. Mutagenesis
of each of the amino-terminal Cys residues to Ala was tolerated only for Cys11, suggesting that these bonds linked the conserved
Cys residues. This was further supported by treatment of intact cells
expressing wild-type or C11A mutant secretin receptor with a
cell-impermeant sulfhydryl-reactive reagent. Thus, the functionally
important amino terminus of the secretin receptor represents a
structurally independent, highly folded, and disulfide-bonded domain,
with a pattern that is likely critical and conserved throughout this receptor family.
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