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Optochemical Approaches for Controlling Protein Dimerization and Protein Function

Courtney, Taylor (2021) Optochemical Approaches for Controlling Protein Dimerization and Protein Function. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Light activation of small molecules, peptides, and proteins is a useful tool for the precise, spatiotemporal control of various biological processes. The incorporation of light-responsive amino acids into proteins in cells and organisms with an expanded genetic code has enabled the precise activation/deactivation of numerous, diverse proteins, such as kinases, nucleases, proteases, and polymerases. Herein, I describe my contributions toward: (1) the application of genetically encoded, photo-activatable cysteine and lysine derivatives for improved understanding of the Ras/Raf/MEK/ERK pathway (specifically, using the dual-specificity phosphatase, MKP3) in mammalian cells, (2) the development of a site-specific light-induced oxidation approach for targeted protein inactivation, and (3) development and application of new, photoswitchable amino acids for future use in controlling metal complex formation.
In addition to the regulation of protein function using light-controlled amino acids, I have contributed to the development of photo-controlled small molecules for manipulating protein dimerization. Rapamycin is a small molecule which dimerizes two proteins, FKBP and FRB, and has been applied for the conditional control of protein-protein interactions. To provide additional levels of control, three different approaches were developed and applied in this thesis: (1) red- shifted caged rapamycin analogs for light-activation of dimerization, (2) ROS-generating analogs for light-inactivation of the ternary complex, and (3) photoswitchable analogs which undergo a configurational change to allow for preferential ternary complex of one isomer over another. The development of these various optically controlled dimerizers expands the range of tools available to chemical biologists for conditional control of protein dimerization.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Courtney, Taylortmc70@pitt.edutmc70
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairDeiters, Alexanderdeiters@pitt.edudeiters
Committee MemberChilders, Sethwschild@pitt.eduwschild
Committee MemberWeber, Stevesweber@pitt.edusweber
Committee MemberYates, Nathanyatesn@pitt.eduyatesn
Date: 20 January 2021
Date Type: Publication
Defense Date: 22 October 2020
Approval Date: 20 January 2021
Submission Date: 27 October 2020
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 389
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: optical control
Date Deposited: 20 Jan 2021 18:28
Last Modified: 20 Jan 2021 18:28
URI: http://d-scholarship.pitt.edu/id/eprint/39822

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