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Format:
Online
Author:
Queen, Katelyn
Dept./Program:
Cellular, Molecular, and Biomedical Sciences Graduate Program
Year:
2023
Degree:
Ph. D.
Abstract:
Kinesins serve critical cellular functions, ranging from intracellular trafficking to cell division and migration. Despite this diversity of functions, kinesins share a conserved enzymatic region consisting of a force producing motor domain and conformation shifting neck-linker. All forty-five mammalian kinesins have post-translational modifications (PTMs) that have been identified within this enzymatic region, however the significance of these PTMs has gone largely unexplored. This work focuses on understanding how PTMs within the motor domain and neck-linker may serve as a broad mechanism of regulation, controlling kinesin localization and function. The mammalian mitotic kinesin KIF18A accumulates at the plus-ends of kinetochore microtubules to facilitate chromosome alignment and promote mitotic progression. Here we address how PTMs within the enzymatic region impact motor properties by focusing on how PTMs within the conserved enzymatic region of KIF18A alter its localization to kinetochore microtubule plus-ends and impact mitotic function. The alpha-4 helix within the motor domain of kinesins is highly conserved, facilitating microtubule binding and contributing to neck-linker docking. Disruption of this helix, by mimicking phosphorylation at S284 or through chemical inhibition, results in altered accumulation of KIF18A to spindle poles and a lack of kinetochore microtubule plus-end accumulation. This altered localization causes defects in chromosome alignment and the formation of multipolar spindles. Chromosomally unstable (CIN) cancer cells have a unique reliance on KIF18A for proliferation. Disrupting the alpha-4 helix through chemical inhibition results in mitotic arrest and proliferation defects in CIN cells, suggesting therapeutic potential in disrupting the alpha-4 helix of KIF18A. The neck-linker of kinesins plays a critical role in promoting progressive unidirectional movement along microtubules. KIF18A has an extended neck-linker that promotes kinetochore microtubule plus-end accumulation. Mimicking phosphorylation at S357 (S357D) in the neck-linker of KIF18A causes the motor to accumulate on peripheral microtubules of the mitotic spindle and decreases the amount of kinetochore microtubule plus-end accumulation. KIF18A S357D expressing cells promote chromosome alignment but exhibit defects in mitotic progression. The altered localization of KIF18A S357D is also accompanied by mitotic spindle instability resulting in abnormal spindle rotations. The phenotypes of KIF18A S357D closely mimic that of a shortened neck-linker (sNL) mutant that also causes accumulation of KIF18A on peripheral microtubules and subsequent mitotic arrest, suggesting KIF18A S357D may adopt a shortened neck-linker like state. This work highlights how post-translational modifications within the enzymatic region of KIF18A serve as a mechanism to control KIF18A localization. Phosphorylation mimetics within the alpha-4 helix or neck-linker result in altered accumulation of KIF18A to a different subset of microtubules. This altered accumulation disrupts the canonical functions of KIF18A, demonstrating the importance of these structural regions for KIF18A function and the potential for regulating kinesin function through PTMs as a mechanism that may be broadly used across the kinesin superfamily.
Note:
Access to this item embargoed until 09/15/2025.