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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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Zhu, Jie. Structural and dynamic investigations of type I collagen and integrin I domains and implications for their interactions. Retrieved from https://doi.org/doi:10.7282/t3-fqyk-pm24

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TitleStructural and dynamic investigations of type I collagen and integrin I domains and implications for their interactions
NameZhu, Jie (author); Baum, Jean (chair); Case, David (co-chair); Khare, Sagar (internal member); Nanda, Vikas (outside member); Rutgers University; School of Graduate Studies
Date Created2018
Other Date2018-10 (degree)
SubjectChemistry and Chemical Biology, Collagen
Extent1 online resource (158 pages : illustrations)
DescriptionIntegrin–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.
NotePh.D.
NoteIncludes bibliographical references
Noteby Jie Zhu
Genretheses, ETD doctoral
Persistent URLhttps://doi.org/doi:10.7282/t3-fqyk-pm24
Languageeng
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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