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Studies on the G-protein regulatory ...

Peterson, Yuri Karl.

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Studies on the G-protein regulatory domain.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Studies on the G-protein regulatory domain./
Author:	Peterson, Yuri Karl.
Description:	215 p.
Notes:	Source: Dissertation Abstracts International, Volume: 65-07, Section: B, page: 3401.
Contained By:	Dissertation Abstracts International65-07B.
Subject:	Health Sciences, Pharmacology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3141140
ISBN:	0496882740

Studies on the G-protein regulatory domain.
Peterson, Yuri Karl.

Studies on the G-protein regulatory domain. - 215 p.

Source: Dissertation Abstracts International, Volume: 65-07, Section: B, page: 3401.

Thesis (Ph.D.)--Louisiana State University Health Sciences Center, 2004.

The G-Protein Regulatory (GPR) motif is a 28 amino acid repeat found in proteins that interact with and regulate heterotrimeric G-proteins. The precise functional role of these proteins in the cell is an area of intense investigation. A GPR consensus peptide was designed based on the GPR domain found within AGS3 and AGS3 family members and influence of the peptide on the activation state of G-protein and receptor coupling to G-protein was determined. The GPR peptide effectively prevented the binding of AGS3 to Gialpha1,2 in protein interaction assays. The GPR peptide inhibited GTPgammaS binding to Gialpha, stabilized the GDP-bound conformation of Gialpha, and blocked receptor coupling to Gialphabetagamma. The GPR peptide had a modest effect on nucleotide binding to Goalpha and brain G-protein, indicating selective regulation of Gialpha. GPR peptides with membrane permeable tags for use in intact cells were then synthesized and characterized. To define the core GPR motif and key amino acid residues, the effect of sequence mutations on peptide-mediated inhibition of GTPgammaS binding to Gialpha1 was determined. The bioactive core GPR peptide consists of 17 amino acids, within which specific microdomains are required for bioactivity. AGS3 is a phosphoprotein and the possibility that phosphorylation is a regulatory mechanism that influences the interaction of AGS3 with G-proteins was explored. Cell lysates specifically phosphorylate GPR domains and phosphorylation can be blocked by a GPR peptide. Individual GPR domains from AGS3 show varying amounts of phosphorylation. A phosphoserine substitution replacing a conserved serine in a GPR peptide decreased the ability of the peptide to inhibit GTPgammaS binding to Gialpha. These data indicate the GPR motif represents an opportunity for selective control and alternative modes of signal input to Gialpha- and Gbetagamma-regulated effector systems. GPR peptides should prove useful as tools for dissecting the functional role of GPR domain containing proteins and offer unique approaches to regulating G-protein function and signaling events. These data also provide a platform for the development of novel, G-protein selective therapeutics that inhibit Gialpha mediated signaling, selectively activate Gbetagamma sensitive effectors and/or disrupt specific regulatory input to G-protein.

ISBN: 0496882740Subjects--Topical Terms:

1017717
Health Sciences, Pharmacology.

Studies on the G-protein regulatory domain.
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100 1 $a Peterson, Yuri Karl. $3 1935502
245 1 0 $a Studies on the G-protein regulatory domain.
300 $a 215 p.
500 $a Source: Dissertation Abstracts International, Volume: 65-07, Section: B, page: 3401.
500 $a Adviser: Stephen Lanier.
502 $a Thesis (Ph.D.)--Louisiana State University Health Sciences Center, 2004.
520 $a The G-Protein Regulatory (GPR) motif is a 28 amino acid repeat found in proteins that interact with and regulate heterotrimeric G-proteins. The precise functional role of these proteins in the cell is an area of intense investigation. A GPR consensus peptide was designed based on the GPR domain found within AGS3 and AGS3 family members and influence of the peptide on the activation state of G-protein and receptor coupling to G-protein was determined. The GPR peptide effectively prevented the binding of AGS3 to Gialpha1,2 in protein interaction assays. The GPR peptide inhibited GTPgammaS binding to Gialpha, stabilized the GDP-bound conformation of Gialpha, and blocked receptor coupling to Gialphabetagamma. The GPR peptide had a modest effect on nucleotide binding to Goalpha and brain G-protein, indicating selective regulation of Gialpha. GPR peptides with membrane permeable tags for use in intact cells were then synthesized and characterized. To define the core GPR motif and key amino acid residues, the effect of sequence mutations on peptide-mediated inhibition of GTPgammaS binding to Gialpha1 was determined. The bioactive core GPR peptide consists of 17 amino acids, within which specific microdomains are required for bioactivity. AGS3 is a phosphoprotein and the possibility that phosphorylation is a regulatory mechanism that influences the interaction of AGS3 with G-proteins was explored. Cell lysates specifically phosphorylate GPR domains and phosphorylation can be blocked by a GPR peptide. Individual GPR domains from AGS3 show varying amounts of phosphorylation. A phosphoserine substitution replacing a conserved serine in a GPR peptide decreased the ability of the peptide to inhibit GTPgammaS binding to Gialpha. These data indicate the GPR motif represents an opportunity for selective control and alternative modes of signal input to Gialpha- and Gbetagamma-regulated effector systems. GPR peptides should prove useful as tools for dissecting the functional role of GPR domain containing proteins and offer unique approaches to regulating G-protein function and signaling events. These data also provide a platform for the development of novel, G-protein selective therapeutics that inhibit Gialpha mediated signaling, selectively activate Gbetagamma sensitive effectors and/or disrupt specific regulatory input to G-protein.
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650 4 $a Biology, Molecular. $3 1017719
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773 0 $t Dissertation Abstracts International $g 65-07B.
790 1 0 $a Lanier, Stephen, $e advisor
790 $a 0854
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856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3141140