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Variations on a Theme: How a Shared ...

Anderson, Brent.

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Variations on a Theme: How a Shared (p)ppGpp Binding Pocket Allows Bacterial Adaptation in Fluctuating Environments.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Variations on a Theme: How a Shared (p)ppGpp Binding Pocket Allows Bacterial Adaptation in Fluctuating Environments./
Author:	Anderson, Brent.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
Description:	333 p.
Notes:	Source: Dissertations Abstracts International, Volume: 82-09, Section: B.
Contained By:	Dissertations Abstracts International82-09B.
Subject:	Microbiology. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=27736344
ISBN:	9798582521358

Variations on a Theme: How a Shared (p)ppGpp Binding Pocket Allows Bacterial Adaptation in Fluctuating Environments.
Anderson, Brent.

Variations on a Theme: How a Shared (p)ppGpp Binding Pocket Allows Bacterial Adaptation in Fluctuating Environments. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 333 p.

Source: Dissertations Abstracts International, Volume: 82-09, Section: B.

Thesis (Ph.D.)--The University of Wisconsin - Madison, 2020.

This item must not be sold to any third party vendors.

Bacteria, from commensals to pathogens, have the capacity to adapt to fluctuating environmental conditions. Key signaling molecules for adaptation are the nucleotide alarmones ppGpp and pppGpp ((p)ppGpp). (p)ppGpp rewires bacterial physiology to conserve energy during stress adaptation and protects bacterial homeostasis by interacting with multiple targets. These targets have evolved across bacterial species to allow them to thrive in different environmental niches. Here we characterize the (p)ppGpp targets HPRT, XPRT, and PurR in Gram-positive bacteria, revealing 1) important mechanisms by which basal and induced (p)ppGpp regulate GTP synthesis and protect the model organism Bacillus subtilis, 2) a new conserved class of (p)ppGpp binding motif that is shared among these targets, and 3) an unexpected strong impact of protein oligomerization on (p)ppGpp target evolution.Using a proteome-wide screen for (p)ppGpp binding proteins, we identify the purine salvage enzyme XPRT and the transcription factor PurR as (p)ppGpp targets in Firmicutes. (p)ppGpp induced by nutrient starvation binds PurR to increase repression of purine nucleotide synthesis genes, decreasing GTP synthesis and likely increasing stress survival. Notably, this is the first evidence of (p)ppGpp directly regulating transcription in Firmicutes. We also show that basal (p)ppGpp, during steady state growth, inhibits the purine salvage enzymes XPRT and HPRT to protect GTP homeostasis against excess extracellular nucleobases.Characterizing the molecular mechanisms of HPRT, XPRT, and PurR regulation by (p)ppGpp reveals two important insights. First, (p)ppGpp shares a PRPP binding motif and competes with the metabolite PRPP for binding each protein. Thus, these proteins comprise a new (p)ppGpp binding motif that may be found in other (p)ppGpp targets. Second, we demonstrate a novel evolutionary mechanism for altering sensitivity of protein targets to (p)ppGpp. We identify two (p)ppGpp targets, HPRT and GMK, that have evolved different sensitivities to (p)ppGpp across bacteria by evolving an allosteric oligomeric interaction rather than altering the (p)ppGpp binding pocket itself. Evolving protein interfaces rather than ligand binding pockets allows proteins to flexibly control (p)ppGpp binding without sacrificing enzymatic activity.Altogether, we show how (p)ppGpp binds a shared pocket in three proteins to regulate GTP synthesis at induced and basal levels, governing bacterial adaptation in rapidly changing environments.

ISBN: 9798582521358Subjects--Topical Terms:

536250
Microbiology.
Subjects--Index Terms:

(p)ppGpp

Variations on a Theme: How a Shared (p)ppGpp Binding Pocket Allows Bacterial Adaptation in Fluctuating Environments.
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500 $a Source: Dissertations Abstracts International, Volume: 82-09, Section: B.
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520 $a Bacteria, from commensals to pathogens, have the capacity to adapt to fluctuating environmental conditions. Key signaling molecules for adaptation are the nucleotide alarmones ppGpp and pppGpp ((p)ppGpp). (p)ppGpp rewires bacterial physiology to conserve energy during stress adaptation and protects bacterial homeostasis by interacting with multiple targets. These targets have evolved across bacterial species to allow them to thrive in different environmental niches. Here we characterize the (p)ppGpp targets HPRT, XPRT, and PurR in Gram-positive bacteria, revealing 1) important mechanisms by which basal and induced (p)ppGpp regulate GTP synthesis and protect the model organism Bacillus subtilis, 2) a new conserved class of (p)ppGpp binding motif that is shared among these targets, and 3) an unexpected strong impact of protein oligomerization on (p)ppGpp target evolution.Using a proteome-wide screen for (p)ppGpp binding proteins, we identify the purine salvage enzyme XPRT and the transcription factor PurR as (p)ppGpp targets in Firmicutes. (p)ppGpp induced by nutrient starvation binds PurR to increase repression of purine nucleotide synthesis genes, decreasing GTP synthesis and likely increasing stress survival. Notably, this is the first evidence of (p)ppGpp directly regulating transcription in Firmicutes. We also show that basal (p)ppGpp, during steady state growth, inhibits the purine salvage enzymes XPRT and HPRT to protect GTP homeostasis against excess extracellular nucleobases.Characterizing the molecular mechanisms of HPRT, XPRT, and PurR regulation by (p)ppGpp reveals two important insights. First, (p)ppGpp shares a PRPP binding motif and competes with the metabolite PRPP for binding each protein. Thus, these proteins comprise a new (p)ppGpp binding motif that may be found in other (p)ppGpp targets. Second, we demonstrate a novel evolutionary mechanism for altering sensitivity of protein targets to (p)ppGpp. We identify two (p)ppGpp targets, HPRT and GMK, that have evolved different sensitivities to (p)ppGpp across bacteria by evolving an allosteric oligomeric interaction rather than altering the (p)ppGpp binding pocket itself. Evolving protein interfaces rather than ligand binding pockets allows proteins to flexibly control (p)ppGpp binding without sacrificing enzymatic activity.Altogether, we show how (p)ppGpp binds a shared pocket in three proteins to regulate GTP synthesis at induced and basal levels, governing bacterial adaptation in rapidly changing environments.
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650 4 $a Molecular biology. $3 517296
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