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The role of the A1 subunit in the activity of shiga toxins
Descriptive
TitleInfo
Title
The role of the A1 subunit in the activity of shiga toxins
Name
(type = personal)
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(type = family)
Basu
NamePart
(type = given)
Debaleena
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Debaleena Basu
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(authority = RULIB)
author
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(type = family)
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Nilgun
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Nilgun Tumer
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Advisory Committee
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chair
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(type = personal)
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(type = family)
White
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(type = given)
James
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James White
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Advisory Committee
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(authority = RULIB)
internal member
Name
(type = personal)
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(type = family)
Belanger
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(type = given)
Faith
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Faith Belanger
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Advisory Committee
Role
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(authority = RULIB)
internal member
Name
(type = personal)
NamePart
(type = family)
Woychik
NamePart
(type = given)
Nancy
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Nancy Woychik
Affiliation
Advisory Committee
Role
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(authority = RULIB)
outside member
Name
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NamePart
Rutgers University
Role
RoleTerm
(authority = RULIB)
degree grantor
Name
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NamePart
Graduate School - New Brunswick
Role
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school
TypeOfResource
Text
Genre
(authority = marcgt)
theses
OriginInfo
DateCreated
(qualifier = exact)
2016
DateOther
(qualifier = exact);
(type = degree)
2016-10
CopyrightDate
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2016
Place
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xx
Language
LanguageTerm
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(type = code)
eng
Abstract
(type = abstract)
Shiga toxin (Stx) producing E.coli infections can lead to life-threatening complications, including hemorrhagic colitis and hemolytic uremic syndrome (HUS). Stx1 and Stx2 are AB5 toxins consisting of an enzymatically active A subunit and a pentamer of receptor binding B subunits. Stx2-producing E.coli strains are more frequently associated with HUS than Stx1-producing strains. The role of the A subunits in the increased potency of Stx2 has not been fully investigated. This study using purified A1 subunits, provide the first direct evidence that the higher affinity for ribosomes in combination with higher catalytic activity towards the SRL allows Stx2A1 to depurinate ribosomes, inhibit translation and exhibit cytotoxicity at a significantly higher level than Stx1A1 in yeast and human cells. To determine if conserved arginines at the distal face of the active site contribute to the higher affinity of Stx2A1 for the ribosome, Arg172, Arg176 and Arg179 in Stx1A1 and Stx2A1 are mutated. It is seen that Arg172 and Arg176 are more important than Arg179 for depurination activity and toxicity of Stx1A1 and Stx2A1. Mutation of at least two of the three arginines is required to significantly reduce depurination by Stx2A1 in vitro and in cells in yeast and mammalian cells. Conserved arginines at the distal face of the active site are critical for interactions of Stx1A1 and Stx2A1 with the stalk, while a conserved arginine at the active site is critical for non-stalk specific interactions with the ribosome. Mutations at conserved arginines at either site reduced ribosome interactions of Stx1A1 and Stx2A1 similarly, indicating that they do not contribute to the higher affinity of Stx2A1 for the ribosome. Interchanging residues E60 and 61 in Stx1A1 and Y60 and Q61 in Stx2A1 that are located away from the active site and ribosome stalk binding site, resulted in small but significant increase in depurination level of E60Y/E61Q for Stx1A1 and a decrease in depurination level of Y60E/Q61E of Stx2A1 in vivo in yeast. A larger difference may be observed if more than two residues are simultaneously altered to change the electrostatic charge distribution of Stx1A1 and Stx2A1 sufficiently.
Subject
(authority = RUETD)
Topic
Plant Biology
Subject
(authority = ETD-LCSH)
Topic
Escherichia coli
Subject
(authority = ETD-LCSH)
Topic
Toxins
RelatedItem
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Title
Rutgers University Electronic Theses and Dissertations
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ETD_7468
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electronic resource
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application/pdf
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text/xml
Extent
1 online resource (xiii, 179 p. : ill.)
Note
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Ph.D.
Note
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Includes bibliographical references
Note
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by Debaleena Basu
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TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
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rucore19991600001
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NjNbRU
Identifier
(type = doi)
doi:10.7282/T3VH5R4T
Genre
(authority = ExL-Esploro)
ETD doctoral
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Rights
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The author owns the copyright to this work.
RightsHolder
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Name
FamilyName
Basu
GivenName
Debaleena
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime
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(qualifier = exact);
(point = start)
2016-08-07 21:37:24
AssociatedEntity
Name
DEBALEENA BASU
Role
Copyright holder
Affiliation
Rutgers University. Graduate School - New Brunswick
AssociatedObject
Type
License
Name
Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
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2016-10-31
DateTime
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2017-10-31
Type
Embargo
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after October 31st, 2017.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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windows xp
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2016-08-09T00:04:46
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2016-08-09T00:04:46
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