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Structural determinants of the canonical Reelin signaling pathway
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Turk, Liam S.. Structural determinants of the canonical Reelin signaling pathway. Retrieved from https://doi.org/doi:10.7282/t3-grz8-7d11

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TitleStructural determinants of the canonical Reelin signaling pathway
NameTurk, Liam S. (author); Comoletti, Davide (chair); Dai, Wei (member); D'Arcangelo, Gabriella (member); Nanda, Vikas (member); Rutgers University; School of Graduate Studies
Date Created2022
Other Date2022-01 (degree)
SubjectBiochemistry, Biophysics, Cryo-ET, Reelin, Structure-function, X-ray crystallography
Extent174 pages : illustrations
DescriptionReelin is a secreted glycoprotein that has well-characterized roles in the developing brain. This ~400 kDa protein is made of several Reelin repeat domains (RRs), exists as a homodimer, and primarily functions through pathways that are stimulated by its interactions with two lipoprotein receptors, VLDLR and ApoER2. Reelin has a complex degradation profile; proteases cleave the protein at two sites, generating up to five Reelin fragments. Of these, the dimeric central fragment (CF) is necessary and sufficient to induce signaling through VLDLR and ApoER2. A monomeric CF construct retains the capacity to bind to the lipoprotein receptors but does not initiate signal transduction. In this thesis, we describe a method to purify a Reelin heterodimeric construct to use as a tool in addressing this inherent decoupling of binding and signaling; we also present the cryo-ET determined structure of Reelin’s dimeric CF, which is independently confirmed using other biophysical and structural techniques. We use these data to form a model of Reelin pathway activation that is dependent on Reelin’s unique dimeric conformation. Furthermore, we present the 3.0 Å resolution crystal structure of RR8. RR8 is the most C-terminal of the RRs, and it is connected to a highly basic stretch of amino acids, termed the C-terminal region (CTR). Peripheral RRs, such as RR8, and the CTR have been receiving more attention in the Reelin community because of their increasingly acknowledged roles in Reelin’s function, regulation, and interactions with proteins other than VLDLR and ApoER2. We highlight general similarities yet discrete differences between the RR8 structure and other, previously solved, three-dimensional RR structures and present data that suggest that the CTR is an intrinsically disordered region at Reelin’s C-terminus.
NotePh.D.
NoteIncludes bibliographical references
Genretheses
Persistent URLhttps://doi.org/doi:10.7282/t3-grz8-7d11
LanguageEnglish
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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