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Strutural [sic] and dynamic NMR studies of the Crk proto-oncogene

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TypeOfResource
Text
TitleInfo (ID = T-1)
Title
Strutural [sic] and dynamic NMR studies of the Crk proto-oncogene
TitleInfo (ID = T-2); (type = alternative)
Title
Structural and dynamic NMR studies of the Crk proto-oncogene
Identifier
ETD_2931
Identifier (type = hdl)
http://hdl.rutgers.edu/1782.1/rucore10001600001.ETD.000056764
Language
LanguageTerm (authority = ISO639-2); (type = code)
eng
Genre (authority = marcgt)
theses
Subject (ID = SBJ-1); (authority = RUETD)
Topic
Chemistry and Chemical Biology
Subject (ID = SBJ-2); (authority = ETD-LCSH)
Topic
Proteins
Subject (ID = SBJ-3); (authority = ETD-LCSH)
Topic
Proteins--Post-translational modification
Subject (ID = SBJ-4); (authority = ETD-LCSH)
Topic
Cytology--Research
Abstract (type = abstract)
The Crk family of adaptor proteins is ubiquitously expressed in most tissues and mediates the timely formation of protein complexes elicited by a variety of extracellular stimuli, including various growth and differentiation factors. This class of proteins lacks an apparent catalytic domain and may serve as adaptors, coupling different proteins of a signal transduction cascade. Crk adaptor proteins are made up of one modular Src homology 2 (SH2) and two Src homology 3 (SH3) domains. SH2 domains bind to phosphotyrosine (pTyr) containing sequence, while SH3 domain binds to proline rich motifs. The two SH3 domains are separated by long linker containing highly conserved proline reisdues. Although the role of SH2 and N-terminal SH3 (SH3N) domains of Crk has been generally delineated, the role of C-terminal SH3 (SH3C) domain remains entirely unknown. There is, however, increasing evidence that the SH3C domain along with the linker act as a regulatory element. Despite the fact that Crk has provided a model system for understanding how adaptor proteins mediate signal transduction, currently the mechanistic basis for the regulation of its function remain elusive. Such an understanding is now rendered evev more urgent because of Crk has been found to be overexpressed in many human cancers. Here, using an integrated NMR, thermodynamic, and biochemical approach, we show the presence of a unique regulatory mechanism in Crk. We have shown hat the SH3C domain serves to regulate the binding activity of the SH3N domain through an intramolecular interaction that is controlled by a prolyl cis/trans isomerization. Proline isomeerization toggles rk between two conformations: an autoinhibitory one, stabilized by the intramolecuar association of the two SH3 domains in the cis form, and an unhibited, activated one prompted by the trans form. The data provides atomic insight into the mechanisms that underpin the functionality of this binary switch and elucidate its remarkable efficiency. The results also demonstrate the interactions are mediated by novel SH3 binding surface. Also, the phosphorylation of the regulatory Tyrosine (Y222) by c-Abl is regulated by another set of prolyl-peptidyl bond, which also serve as a substrate for Cyclophilin A (CypA).
PhysicalDescription
Form (authority = gmd)
electronic resource
Extent
xxiii, 160 p. : ill.
InternetMediaType
application/pdf
InternetMediaType
text/xml
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
Note (type = vita)
Includes vita
Note (type = statement of responsibility)
by Paramita Sarkar
Name (ID = NAME-1); (type = personal)
NamePart (type = family)
Sarkar
NamePart (type = given)
Paramita
NamePart (type = date)
1979-
Role
RoleTerm (authority = RULIB)
author
DisplayForm
Paramita Sarkar
Name (ID = NAME-2); (type = personal)
NamePart (type = family)
Baum
NamePart (type = given)
Jean
Role
RoleTerm (authority = RULIB)
chair
Affiliation
Advisory Committee
DisplayForm
Jean Baum
Name (ID = NAME-3); (type = personal)
NamePart (type = family)
Kalodimos
NamePart (type = given)
Charalampos G
Role
RoleTerm (authority = RULIB)
co-chair
Affiliation
Advisory Committee
DisplayForm
Charalampos G Kalodimos
Name (ID = NAME-4); (type = personal)
NamePart (type = family)
Case
NamePart (type = given)
David A
Role
RoleTerm (authority = RULIB)
internal member
Affiliation
Advisory Committee
DisplayForm
David A Case
Name (ID = NAME-5); (type = personal)
NamePart (type = family)
Birge
NamePart (type = given)
Raymond B
Role
RoleTerm (authority = RULIB)
outside member
Affiliation
Advisory Committee
DisplayForm
Raymond B Birge
Name (ID = NAME-1); (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (ID = NAME-2); (type = corporate)
NamePart
Graduate School - New Brunswick
Role
RoleTerm (authority = RULIB)
school
OriginInfo
DateCreated (qualifier = exact)
2010
DateOther (qualifier = exact); (type = degree)
2010-10
Place
PlaceTerm (type = code)
xx
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
RelatedItem (type = host)
TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier (type = local)
rucore19991600001
Location
PhysicalLocation (authority = marcorg); (displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
Identifier (type = doi)
doi:10.7282/T37P8Z34
Genre (authority = ExL-Esploro)
ETD doctoral
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Rights

RightsDeclaration (AUTHORITY = GS); (ID = rulibRdec0006)
The author owns the copyright to this work.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
RightsHolder (ID = PRH-1); (type = personal)
Name
FamilyName
Sarkar
GivenName
Paramita
Role
Copyright Holder
RightsEvent (ID = RE-1); (AUTHORITY = rulib)
Type
Permission or license
DateTime
2010-09-28 19:30:53
AssociatedEntity (ID = AE-1); (AUTHORITY = rulib)
Role
Copyright holder
Name
Paramita Sarkar
Affiliation
Rutgers University. Graduate School - New Brunswick
AssociatedObject (ID = AO-1); (AUTHORITY = rulib)
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.
RightsEvent (ID = RE-2); (AUTHORITY = rulib)
Type
Embargo
DateTime
2010-10-31
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after May 2nd, 2011.
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Technical

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ETD
MimeType (TYPE = file)
application/pdf
MimeType (TYPE = container)
application/x-tar
FileSize (UNIT = bytes)
4526080
Checksum (METHOD = SHA1)
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