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Author ORCID Identifier

0000-0002-5673-878X

AccessType

Campus-Only Access for Five (5) Years

Document Type

dissertation

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Molecular and Cellular Biology

Year Degree Awarded

2022

Month Degree Awarded

September

First Advisor

Margaret Stratton

Subject Categories

Biochemistry | Biophysics | Structural Biology

Abstract

Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a serine/threonine kinase that has been shown to carry out various crucial cellular processes. In the basal state of the cells, CaMKII stays autoinhibited, which then can be reversed with the initiation of calcium influx. CaMKII is very well characterized by two canonical ways of maintaining its active state: Ca2+/CaM binding and autophosphorylation at Thr286 residue. Later, it has been shown that CaMKII can maintain its active state through several interaction partners even in the absence of calcium signaling or autophosphorylation. A two-site binding model has been proposed to explain this phenomenon. We have solved cocrystal structures of CaMKII with a set of interaction partners that rendered a two-site binding model very unlikely. We further characterized the interactions with these binding partners biochemically and biophysically and proposed a new model. Another intriguing property of CaMKII is its ability to form high order oligomeric structures. Previously, a crystal structure of full length CaMKIIα has been published revealing autoinhibition and activation properties of the holoenzyme. CaMKII kinase domains were reported as docked on their own hub domains in that study. We obtained a crystal structure of full length CaMKIIδ that indicated CaMKII subunits swaps kinase domains with another. This new finding has potentially interesting implications on CaMKII activation properties with the consideration of its highly cooperative nature.

DOI

https://doi.org/10.7275/31055894

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

Available for download on Friday, September 01, 2023

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