Article (Scientific journals)
The Human Vpac(1) Receptor - Three-Dimensional Model And Mutagenesis Of The N-Terminal Domain
Lins, Laurence; Couvineau, A.; Rouyer-Fessard, C. et al.
2001In Journal of Biological Chemistry, 276 (13), p. 10153-10160
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Abstract :
[en] The human VPAC(1) receptor for vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating peptide belongs to the class II family of G-protein-coupled receptors with seven transmembrane segments. Like for all class II receptors, the extracellular N-terminal domain of the human VPAC(1) receptor plays a predominant role in peptide ligand recognition. To determine the three-dimensional structure of this N-terminal domain (residues 1-144), the Protein Data Bank (PDB) was screened for a homologous protein. A subdomain of yeast lipase B was found to have 27% sequence identity and 50% sequence homology with the N-terminal domain (8) of the VPAC(1) receptor together with a good alignment of the hydrophobic clusters. A model of the N-terminal domain of VPAC(1) receptor was thus constructed by homology. It indicated the presence of a putative signal sequence in the N-terminal extremity. Moreover, residues (Glu(36), Trp(67), Asp(68), Trp(73), and Gly(109)) which were shown to be crucial for VIP binding are gathered around a groove that is essentially negatively charged. New putatively important residues for VIP binding were suggested from the model analysis. Site-directed mutagenesis and stable transfection of mutants in CHO cells indicated that Pro(74), Pro(87), Phe(90), and Trp(110) are indeed important for VIP binding and activation of adenylyl cyclase activation. Combination of molecular modeling and directed mutagenesis provided the first partial three-dimensional structure of a VIP-binding domain, constituted of an electronegative groove with an outspanning tryptophan shell at one end, in the N-terminal extracellular region of the human VPAC(1) receptor.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Lins, Laurence  ;  Université de Liège - ULiège > Gembloux Agro-Bio Tech
Couvineau, A.
Rouyer-Fessard, C.
Nicole, P.
Maoret, Jj.
Benhamed, M.
Brasseur, Robert ;  Université de Liège - ULiège > Gembloux Agro-Bio Tech
Thomas, Annick ;  Université de Liège - ULiège > Chimie et bio-industries > Centre de Bio. Fond. - Section de Biologie moléc. et numér.
Laburthe, M.
Language :
English
Title :
The Human Vpac(1) Receptor - Three-Dimensional Model And Mutagenesis Of The N-Terminal Domain
Publication date :
2001
Journal title :
Journal of Biological Chemistry
ISSN :
0021-9258
eISSN :
1083-351X
Publisher :
American Society for Biochemistry and Molecular Biology, United States - Maryland
Volume :
276
Issue :
13
Pages :
10153-10160
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 24 June 2010

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