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Structural and dynamic investigations of type I collagen and integrin I domains and implications for their interactions
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TitleInfo
Title
Structural and dynamic investigations of type I collagen and integrin I domains and implications for their interactions
Name
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NamePart
(type = family)
Zhu
NamePart
(type = given)
Jie
NamePart
(type = date)
1988-
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Jie Zhu
Role
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(authority = RULIB)
author
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Baum
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Jean
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Jean Baum
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Advisory Committee
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chair
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David
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David Case
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Advisory Committee
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co-chair
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(type = family)
Khare
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Sagar
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Sagar Khare
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Advisory Committee
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(authority = RULIB)
internal member
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(type = personal)
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(type = family)
Nanda
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Vikas
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Vikas Nanda
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Advisory Committee
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outside member
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Rutgers University
Role
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(authority = RULIB)
degree grantor
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School of Graduate Studies
Role
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school
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Text
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theses
OriginInfo
DateCreated
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2018
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2018-10
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2018
Place
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xx
Language
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eng
Abstract
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Integrin–collagen interactions play a critical role in numerous cellular functions. In this dissertation, the structures, dynamics, and interactions of the type I collagen and integrin I domains are investigated. The objective is to gain insight into the mechanism of the collagen–integrin interactions.
Collagen fibril interactions with cells and macromolecules in the extracellular matrix drive numerous cellular functions. Binding motifs for dozens of collagen-binding proteins have been determined on fully exposed collagen triple helical monomers. However, when the monomers are assembled into the functional collagen fibril, binding motifs become inaccessible, and yet critical cellular processes continue to occur. Here we use an integrative approach by combining molecular dynamics (MD) simulations with atomic force microscopy (AFM) experiments and show that fluctuations of the collagen monomers within the complex fibril play a critical role in collagen interactions.
To better understand the mechanisms underlying collagen-induced conformational switches of integrin I domains, we employ NMR hydrogen-deuterium exchange (HDX) experiments to explore the impact of slower timescale dynamic events. NMR HDX results suggest a relationship between regions exhibiting a reduced local stability in the unbound I domain and those that undergo significant conformational changes upon binding. This study supports a model in which intrinsically destabilized regions predispose conformational rearrangement in the integrin I domain.
The morphology and mechanical properties of type I collagen fibrils vary greatly in different tissues. Integrins have been proposed to regulate the type I collagen fibrillogenesis in vivo. Here we report on the type I collagen fibrillogenesis affected by integrin I domains and mutants. The conducted experiments showed that integrins and variants slowed down the kinetics of type I collagen fibril formation and reduced the sizes of the immature fibrils. The gain-of-function mutants inhibited the fusions of fibrils. Enhanced viscosities of collagen gels were observed in the presence of integrin I domains, implying stronger interactions between collagen fibrils. We propose that in vivo, integrins of different activation states might regulate collagen fibrillogenesis.
Collagen fibril interactions with cells and macromolecules in the extracellular matrix drive numerous cellular functions. Binding motifs for dozens of collagen-binding proteins have been determined on fully exposed collagen triple helical monomers. However, when the monomers are assembled into the functional collagen fibril, binding motifs become inaccessible, and yet critical cellular processes continue to occur. Here we use an integrative approach by combining molecular dynamics (MD) simulations with atomic force microscopy (AFM) experiments and show that fluctuations of the collagen monomers within the complex fibril play a critical role in collagen interactions.
To better understand the mechanisms underlying collagen-induced conformational switches of integrin I domains, we employ NMR hydrogen-deuterium exchange (HDX) experiments to explore the impact of slower timescale dynamic events. NMR HDX results suggest a relationship between regions exhibiting a reduced local stability in the unbound I domain and those that undergo significant conformational changes upon binding. This study supports a model in which intrinsically destabilized regions predispose conformational rearrangement in the integrin I domain.
The morphology and mechanical properties of type I collagen fibrils vary greatly in different tissues. Integrins have been proposed to regulate the type I collagen fibrillogenesis in vivo. Here we report on the type I collagen fibrillogenesis affected by integrin I domains and mutants. The conducted experiments showed that integrins and variants slowed down the kinetics of type I collagen fibril formation and reduced the sizes of the immature fibrils. The gain-of-function mutants inhibited the fusions of fibrils. Enhanced viscosities of collagen gels were observed in the presence of integrin I domains, implying stronger interactions between collagen fibrils. We propose that in vivo, integrins of different activation states might regulate collagen fibrillogenesis.
Subject
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Topic
Chemistry and Chemical Biology
Subject
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Topic
Collagen
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Rutgers University Electronic Theses and Dissertations
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ETD_9303
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electronic resource
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1 online resource (158 pages : illustrations)
Note
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Ph.D.
Note
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Includes bibliographical references
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by Jie Zhu
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School of Graduate Studies Electronic Theses and Dissertations
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rucore10001600001
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NjNbRU
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doi:10.7282/t3-fqyk-pm24
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(authority = ExL-Esploro)
ETD doctoral
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Rights
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The author owns the copyright to this work.
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Name
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Zhu
GivenName
Jie
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Permission or license
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2018-10-03 12:00:16
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Jie Zhu
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Rutgers University. School of Graduate Studies
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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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2018-10-31
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2020-10-30
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after October 30th, 2020.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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