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Article: Isolation and structure-function studies of a glucagon-like peptide 1 receptor from goldfish Carassius auratus: Identification of three charged residues in extracellular domains critical for receptor function

TitleIsolation and structure-function studies of a glucagon-like peptide 1 receptor from goldfish Carassius auratus: Identification of three charged residues in extracellular domains critical for receptor function
Authors
Issue Date2002
PublisherThe Endocrine Society. The Journal's web site is located at http://endo.endojournals.org
Citation
Endocrinology, 2002, v. 143 n. 12, p. 4646-4654 How to Cite?
AbstractA better understanding of the molecular mechanism of ligand-receptor interaction of glucagon-like peptide 1 (GLP-1) receptors (GLP-1Rs) is useful for the design of potent GLP-1 analogs that could potentially be used as a treatment for diabetic patients. Changes in the ligand and receptor sequences during evolution provide invaluable clues to evaluate the functional motifs of the receptor that are responsible for ligand interaction. For these reasons, in the present study, we have isolated and functionally characterized a GLP-1R from goldfish. Its amino acid sequence shows 50.8% and 52.3% identity with the human glucagon (hGLU) and GLP-1Rs, respectively, and 84.1% with the zebrafish GLP-1R (the only other GLP-1R isolated from teleost fish). Peptides that are structurally different from goldfish (gf)GLP-1, such as gfGLU and hGLU and human GLP-1 (7-36)amide, are also capable of stimulating this receptor, albeit with lower potencies than gfGLP-1, gfGLP-1 stimulates the formation of cAMP through the recombinant gfGLP-1R with EC50 = 0.18 nM, whereas EC50 values for gfGLU, human GLP-1 (7-36)amide, and hGLU are 0.53 nM, 0.9 nM, and 1.2 nM, respectively. These results indicate that the gfGLP-1R is structurally more flexible than its mammalian counterpart and that its binding pocket can accommodate a wider spectrum of peptide ligands. Previous studies demonstrated that the charged residues in the extracellular domains of mammalian GLP-1R, particularly those found in the N-terminal domain and the first exoloop, are important for ligand binding. We investigated the roles of the conserved charged residues in the function of the gfGLP-1R. Eleven mutant receptors were constructed, and the effects of mutations were determined by functional assays. Our results demonstrated that three charged residues (D113, R197, and D205) present in the extracellular domains are critical for receptor function.
Persistent Identifierhttp://hdl.handle.net/10722/84809
ISSN
2015 Impact Factor: 4.159
2015 SCImago Journal Rankings: 2.363
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorYeung, CMen_HK
dc.contributor.authorMojsov, Sen_HK
dc.contributor.authorMok, PYen_HK
dc.contributor.authorChow, BKCen_HK
dc.date.accessioned2010-09-06T08:57:22Z-
dc.date.available2010-09-06T08:57:22Z-
dc.date.issued2002en_HK
dc.identifier.citationEndocrinology, 2002, v. 143 n. 12, p. 4646-4654en_HK
dc.identifier.issn0013-7227en_HK
dc.identifier.urihttp://hdl.handle.net/10722/84809-
dc.description.abstractA better understanding of the molecular mechanism of ligand-receptor interaction of glucagon-like peptide 1 (GLP-1) receptors (GLP-1Rs) is useful for the design of potent GLP-1 analogs that could potentially be used as a treatment for diabetic patients. Changes in the ligand and receptor sequences during evolution provide invaluable clues to evaluate the functional motifs of the receptor that are responsible for ligand interaction. For these reasons, in the present study, we have isolated and functionally characterized a GLP-1R from goldfish. Its amino acid sequence shows 50.8% and 52.3% identity with the human glucagon (hGLU) and GLP-1Rs, respectively, and 84.1% with the zebrafish GLP-1R (the only other GLP-1R isolated from teleost fish). Peptides that are structurally different from goldfish (gf)GLP-1, such as gfGLU and hGLU and human GLP-1 (7-36)amide, are also capable of stimulating this receptor, albeit with lower potencies than gfGLP-1, gfGLP-1 stimulates the formation of cAMP through the recombinant gfGLP-1R with EC50 = 0.18 nM, whereas EC50 values for gfGLU, human GLP-1 (7-36)amide, and hGLU are 0.53 nM, 0.9 nM, and 1.2 nM, respectively. These results indicate that the gfGLP-1R is structurally more flexible than its mammalian counterpart and that its binding pocket can accommodate a wider spectrum of peptide ligands. Previous studies demonstrated that the charged residues in the extracellular domains of mammalian GLP-1R, particularly those found in the N-terminal domain and the first exoloop, are important for ligand binding. We investigated the roles of the conserved charged residues in the function of the gfGLP-1R. Eleven mutant receptors were constructed, and the effects of mutations were determined by functional assays. Our results demonstrated that three charged residues (D113, R197, and D205) present in the extracellular domains are critical for receptor function.en_HK
dc.languageengen_HK
dc.publisherThe Endocrine Society. The Journal's web site is located at http://endo.endojournals.orgen_HK
dc.relation.ispartofEndocrinologyen_HK
dc.rightsEndocrinology. Copyright © The Endocrine Society.en_HK
dc.titleIsolation and structure-function studies of a glucagon-like peptide 1 receptor from goldfish Carassius auratus: Identification of three charged residues in extracellular domains critical for receptor functionen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0013-7227&volume=143&spage=4646&epage=4654&date=2002&atitle=Isolation+and+Structure-Function+Studies+of+a+Glucagon-Like+Peptide+1+Receptor+from+Goldfish+Carassius+auratus:+Identification+of+Three+Charged+Residues+in+Extracellular+Domains+Critical+for+Receptor+Functionen_HK
dc.identifier.emailChow, BKC: bkcc@hku.hken_HK
dc.identifier.authorityChow, BKC=rp00681en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1210/en.2002-220694en_HK
dc.identifier.pmid12446592-
dc.identifier.scopuseid_2-s2.0-0036892893en_HK
dc.identifier.hkuros75610en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0036892893&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume143en_HK
dc.identifier.issue12en_HK
dc.identifier.spage4646en_HK
dc.identifier.epage4654en_HK
dc.identifier.isiWOS:000179543900020-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridYeung, CM=7201354151en_HK
dc.identifier.scopusauthoridMojsov, S=7004216736en_HK
dc.identifier.scopusauthoridMok, PY=36884813000en_HK
dc.identifier.scopusauthoridChow, BKC=7102826193en_HK

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