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Structural investigations of the reg...

Slep, Kevin Charles.

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Structural investigations of the regulator of G-protein signaling family of GTPase activating proteins.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Structural investigations of the regulator of G-protein signaling family of GTPase activating proteins./
作者:	Slep, Kevin Charles.
面頁冊數:	158 p.
附註:	Directors: Paul B. Sigler; Andrew Miranker.
Contained By:	Dissertation Abstracts International61-10B.
標題:	Biophysics, General. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=9991230
ISBN:	0599983876

Structural investigations of the regulator of G-protein signaling family of GTPase activating proteins.
Slep, Kevin Charles.

Structural investigations of the regulator of G-protein signaling family of GTPase activating proteins. - 158 p.

Directors: Paul B. Sigler; Andrew Miranker.

Thesis (Ph.D.)--Yale University, 2000.

Presented here is conclusive biochemical and structural data that elucidates the mechanism behind the regulator of G-protein signaling (RGS) family of GTPase activating proteins. Five structures have been determined: (1) the RGSr RGS domain, (2) the RGSr RGS domain in complex with Goα, (3) the RGS9 RGS domain, (4) the RGS9 RGS domain in complex with the chimeric Gt/il α subunit, and (5) the visual system's heterotrimeric effector/GAP complex: Gt/ilα·GDP·AlF 4<super>–</super>·PDEγ·RGS9. RGS proteins augment the Gα subunit's intrinsic rate of hydrolysis by stabilizing the Gα switch regions in the transition state conformation. In addition, the RGS domain makes two key interactions: one to the Gα subunit's switch II glutamine involved in GTP hydrolysis and a second to the backbone of switch I. In both cases, the interactions with the RGS protein orient Gα carbonyls used to position the nucleophilic water for optimal attack on the GTP γ-phosphate. Through these interactions, the RGS protein enhances the rate of GTP hydrolysis.

ISBN: 0599983876Subjects--Topical Terms:

1019105
Biophysics, General.

Structural investigations of the regulator of G-protein signaling family of GTPase activating proteins.
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245 1 0 $a Structural investigations of the regulator of G-protein signaling family of GTPase activating proteins.
300 $a 158 p.
500 $a Directors: Paul B. Sigler; Andrew Miranker.
500 $a Source: Dissertation Abstracts International, Volume: 61-10, Section: B, page: 5303.
502 $a Thesis (Ph.D.)--Yale University, 2000.
520 $a Presented here is conclusive biochemical and structural data that elucidates the mechanism behind the regulator of G-protein signaling (RGS) family of GTPase activating proteins. Five structures have been determined: (1) the RGSr RGS domain, (2) the RGSr RGS domain in complex with Goα, (3) the RGS9 RGS domain, (4) the RGS9 RGS domain in complex with the chimeric Gt/il α subunit, and (5) the visual system's heterotrimeric effector/GAP complex: Gt/ilα·GDP·AlF 4<super>–</super>·PDEγ·RGS9. RGS proteins augment the Gα subunit's intrinsic rate of hydrolysis by stabilizing the Gα switch regions in the transition state conformation. In addition, the RGS domain makes two key interactions: one to the Gα subunit's switch II glutamine involved in GTP hydrolysis and a second to the backbone of switch I. In both cases, the interactions with the RGS protein orient Gα carbonyls used to position the nucleophilic water for optimal attack on the GTP γ-phosphate. Through these interactions, the RGS protein enhances the rate of GTP hydrolysis.
520 $a The higher order complex of Gt/ilα·GDP·A1F 4<super>–</super>·PDEγRGS9 reveals the visual system's mechanisms of effector activation, effector/GAP coupling and GAP potentiation. PDEγ binds the nucleotide-dependent Gt/il α switch II/α3 region. Upon binding, the PDEγ C-terminal region, implicated in PDEαβ inhibition, is sequestered by Gt/ilα. Removal of the inhibitory constraints imposed by PDEγ allows PDEαβ to proceed with cGMP catalysis, effectively propagating the visual signal. In its sequestered state, PDEγ potentiates the recruitment of RGS9 by augmenting the available binding site. In addition, the PDEγ residue Trp70 perturbs structural elements of the Gt/ilα active site into a conformation that favors the transition state. Recruitment of RGS9 produces a concomitant GAP activity that inactivates Gt/ilα. In the GDP-bound state, the Gt/ilα switch II region undergoes a large conformational change that disrupts the PDEγ binding site. PDEγ is released, returns to the inhibitory site on PDEαβ and quenches the hydrolysis of cGMP. This mechanism of effector/GAP coupling in the mammalian visual system affords a highly damped signaling system, indicative of the visual system's temporal resolution and wide dynamic range.
520 $a In addition to determining the mechanisms behind RGS GAP activity and effector/GAP coupling in the visual system, these studies also reveal (1) minor conformational changes that occur to the RGS domain upon binding the Gα subunit, (2) mechanisms of RGS specificity, and (3) novel structural features of the neuronal G-protein, Goα.
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