Recognition and signal transduction mechanism of Escherichia coli heat-stable enterotoxin and its receptor, guanylate cyclase C
: Guanylate cyclase C (GC‐C), a member of the membrane‐bound GC family, consists of an extracellular domain (ECD) and an intracellular domain, which are connected by a single‐transmembrane region. GC‐C is a receptor protein, i.e. specifically stimulated by the endogenous peptides guanylin, uroguany...
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Veröffentlicht in: | The journal of peptide research 2005-02, Vol.65 (2), p.261-271 |
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Sprache: | eng |
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Zusammenfassung: | : Guanylate cyclase C (GC‐C), a member of the membrane‐bound GC family, consists of an extracellular domain (ECD) and an intracellular domain, which are connected by a single‐transmembrane region. GC‐C is a receptor protein, i.e. specifically stimulated by the endogenous peptides guanylin, uroguanylin, lymphoguanylin, and the exogenous peptide heat‐stable enterotoxin (STa), secreted by pathogenic Escherichia coli and acting on the intestinal brush border membranes. The binding of these peptide ligands to the ECD of GC‐C results in the synthesis of cyclic GMP in cells, which, in turn, regulates a variety of intracellular physiologic processes. As the cloning of GC‐C, its physiologic functions of each domain have been vigorously investigated. The structural characterization of the ligand‐binding domain of the receptor promises to provide important clues for better understanding of the mechanisms of receptor recognition and activation. Recently, structural data for each domain of membrane‐bound GCs and related proteins has become available. Coupling information obtained from such work and validation of structure–function relationships of GC‐C and its ligands should allow for three‐dimensional mapping of their interaction site in detail. Our approach to this issue involved designing photoaffinity‐labeling STa analogs, capable of binding covalently to the ligand‐binding region of the ECD of GC‐C. The photoaffinity‐labeling ligand was used to covalently label a soluble form of the recombinant ECD protein. Mass spectrometric analyses of an endoproteinase digest of the ECD revealed that the ligand specifically bound to a narrow region contained in the membrane‐proximal subdomain of the ECD of GC‐C. These results will enable us to identify the possible binding motifs within the ligand‐binding domain by computer modeling. In this review, we summarize the available data on the recognition mechanism between STa and GC‐C at the molecular level. |
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ISSN: | 1397-002X 1399-3011 |
DOI: | 10.1111/j.1399-3011.2005.00218.x |