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Presented By: LSA Biophysics

Zhenyu Tan Dissertation Defense

Zhenyu Tan

TITLE: Kinesin regulation via kinesin binding protein (KIFBP) and autoinhibition

ABSTRACT: The spatiotemporal regulation of organelle positioning is critical for proper cellular function, especially as the cell responds to a changing environment. A key player in this process is the kinesin superfamily of motor proteins. These proteins participate in a diverse range of cellular processes, from facilitating long-range axonal transport to orchestrating the mitotic spindle during
cell division. The regulation of kinesin motor proteins occurs via inhibitory and activation-based mechanisms, where kinesin motor proteins are subject to autoinhibition when not bound to a cargo.
Recently, the discovery of the kinesin-binding protein (KIFBP) revealed a novel form of kinesin inhibition, in which KIFBP binds to kinesin motor domains to block microtubule-binding. Cell biological studies indicate that both autoinhibition and KIFBP-mediated inhibition are critical for proper cellular function. However, there remains little consensus and conflicting reports on the molecular mechanism of kinesin autoinhibition due to a lack of structural information on fulllength kinesin motors. Moreover, the mechanism governing the KIFBP inhibition is poorly defined. In my Ph.D. research, I applied integrative structural analysis to determine how
autoinhibition and KIFBP-mediated inhibition occurs at molecular levels. My research project on kinesin-1 autoinhibition revised the established model in the field by offering the first comprehensive description of kinesin-1 autoinhibition (Tan et al. eLife 2023). Kinesin-1, discovered nearly 40 years ago, was the first identified kinesin and serves as a model for understanding kinesin function. A widely accepted model of kinesin-1 autoinhibition is that the C-terminal tail of kinesin-1 drives autoinhibition to block motility. However, published data suggested that the tail may not be the sole determinant of autoinhibition. To uncover the molecular
mechanism of kinesin-1 autoinhibition, I combined AlphaFold protein structure prediction, electron microscopy and cross-linking mass spectrometry to reveal the molecular architecture of autoinhibited kinesin-1. My findings revised the previous model and showed that multiple intramolecular contacts within the kinesin-1 lead to an inhibited state. My work provides a framework to understand why kinesin-1 activation requires cargo adaptors and microtubule-associated proteins to bind to and compete with intramolecular association to produce an open,
active motor. My second project aimed to investigate kinesin binding protein (KIFBP), a newly identified regulatory binding partner of kinesins. KIFBP exhibits the remarkable ability to associate and inhibit specific members of the kinesin superfamily. Mutations to KIFBP in humans have been linked to the neurological disorder Goldberg-Shprintzen (GOSHS) syndrome. Despite the clinical
relevance of KIFBP, it remains unclear how KIFBP binds kinesins, how it achieves specificity for a subset of kinesins, and which kinesin(s) are responsible for the phenotypes seen in GOSHS. To characterize the mechanism of kinesin regulation through KIFBP, I determined cryo-EM structures of KIFBP alone at 3.8Å and KIFBP bound to two different kinesin motors at 4.5-4.9Å. I used de novo atomic modeling along with Phenix and Rosetta to develop a model for the KIFBP-engaged
kinesin motors. My structures provided the first atomistic view of kinesin engaged by KIFBP, showing that, KIFBP remodels and displaces the microtubules binding helix from kinesins to block microtubule binding. My work (Solon, Tan, et al. Science Advances 2021) paves the way for a deeper understanding of how KIFBP regulates its subset of kinesins, how it achieves specificity in binding, and how it contributes to GOSHS

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