Speaker:

Professor Casper Hoogenraad
Vice President (Neuroscience)
Genentech, South San Francisco, USA

Title: "Mechanisms of cargo trafficking: cytoskeleton organization and motor regulation"

Abstract:

In order to transport cargos, such as synaptic vesicles, mitochondria, neurotransmitter receptors and signaling proteins, neurons make use of molecular motor proteins. These motors operate on the microtubule and actin cytoskeleton and are highly regulated so that different cargos can be transported to the axon, dendrites and synaptic sites. How cargo transport is spatially and temporally controlled remains largely unknown. Precise control of dynein and kinesin motors is important to ensure proper synaptic cargo transport and misregulation often leads to severe human neurological and neurodegenerative disorders.
Homozygous nonsense mutations in kinesin-binding protein (KBP) cause the neurological disorder Goldberg-Shprintzen syndrome (GOSHS), which is characterized by intellectual disability, microcephaly, synaptic vesicle accumulations and axonal neuropathy. Previously we have shown that KBP regulates kinesin activity by interacting with the motor domains of a specific subset of kinesins to prevent their association with the microtubule cytoskeleton. The KBP-interacting kinesins include cargo-transporting motors such as kinesin-12/KIF15 and kinesin-3/KIF1A. We found that KBP blocks KIF1A-mediated synaptic vesicle transport in cultured hippocampal neurons and in C. elegans PVD sensory neurons. In contrast, depletion of KBP results in the accumulation of KIF1A motors and synaptic vesicles in the axonal growth cone. Our cell biological data suggest that KBP functions as a selective kinesin inhibitor by buffering the activity of a subset of kinesins. Together with Carolyn Moores’ group, we further investigated the molecular basis for KBP-kinesin selectivity and solved the cryo-electron structure of KBP and a KBP-kinesin motor domain complex. KBP is a tetratricopeptide repeat-containing, right-handed α-solenoid that sequesters the kinesin motor domain's tubulin-binding surface, structurally distorting the motor domain and sterically blocking its microtubule attachment. The KBP-interacting motor domain surface contains motifs exclusively conserved in KBP-interacting kinesins, suggesting a basis for kinesin selectivity. The structural characterization of the KBP–kinesin inhibitory interaction provides an important mechanistic platform to further understand kinesin motor regulation.
 

About Neuroscience Seminars

Neuroscience seminars at the QBI play a major role in the advancement of neuroscience in the Asia-Pacific region. The primary goal of these seminars is to promote excellence in neuroscience through the exchange of ideas, establishing new collaborations and augmenting partnerships already in place.

While seminars in the QBI Auditorium have been suspended due to COVID-19, we will still be holding seminars via Zoom. The days and times of these seminars will vary depending on the time zone of the speaker. Please see each seminar listed below for details. 

 

Neuroscience Seminars archive 2005-2018