Cargo Specific Regulation Of Cytoplasmic Dynein By Effector Proteins

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Doctor of Philosophy (PhD)
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Biochemistry & Molecular Biophysics
Cell Biology
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Axonal transport is vital for the development and survival of neurons. The transport of cargo and organelles from the axon to the cell body is driven almost completely by the molecular motor, cytoplasmic dynein. Yet, it remains unclear how dynein is spatially and temporally regulated given the variety of cargo that must be properly localized to maintain cellular function. Previous work has suggested that adaptor proteins provide a mechanism for cargo-specific regulation of motors. During my thesis work, I have investigated the role of mammalian Hook proteins, Hook1 and Hook3, as potential motor adaptors. Using optogenetic and single molecule assays, I found that Hook proteins interact with both dynein and dynactin, to effectively activate dynein motility, inducing longer run lengths and higher velocities than the previously characterized dynein activator, BICD2. In addition, I found that complex formation requires the N-terminal domain of Hook proteins, which resembles the calponin-homology domain of EB proteins yet cannot bind directly to microtubules. In collaborative studies, we found the Hook domain directly interacts with a helix of the dynein light intermediate chain and this interaction is important for Hook-induced processive motility of dynein. In my final project, I found that Hook1 mediates the transport of TrkB-BDNF signaling endosomes in primary hippocampal neurons. Using live cell microscopy and microfluidic devices, Hook1 depletion resulted in a significant decrease in the flux and processivity of BDNF-Qdots along the mid-axon, an effect specific for Hook1 but not Hook3. Together, my work suggests that dynein effectors like Hook proteins can differentially regulate dynein to allow for organelle-specific tuning of the motor for precise intracellular trafficking.

Erika L. Holzbaur
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