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Neurons depend on proper localization of neurotrophic receptors in their distal processes for their function. The Trk family of neurotrophin receptors controls neuronal survival, differentiation, and remodeling and are well known to function as retrograde signal carriers transported from the distal axon toward the cell body. However, the mechanism driving anterograde trafficking of Trk receptors into the axon is not well established. We used microfluidic compartmental devices and inducible secretion assay to systematically investigate the retrograde and anterograde trafficking routes of TrkB receptor along the axon in rat hippocampal neurons. We show that newly synthesized TrkB receptors traffic through the secretory pathway and are directly delivered into axon. We found that these TrkB carriers associate and are regulated by Rab6. Furthermore, the combined activity of kinesin-1 and kinesin-3 is needed for the formation of axon-bound TrkB secretory carriers and their effective entry and processive anterograde transport beyond the proximal axon.
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http://dx.doi.org/10.1016/j.devcel.2021.01.010 | DOI Listing |
Trafficking of intracellular cargoes along the neuronal axon microtubule tracks is a motor-protein-dependent process. It is well-established that the motor protein kinesin is responsible for anterograde trafficking of axonal cargo, while the dynein/dynactin complex regulates retrograde trafficking. However, there is still much to uncover regarding the various isoforms of these motor proteins as well as the adapter and cargo-associated proteins involved in the precise trafficking dynamics.
View Article and Find Full Text PDFBiomolecules
May 2025
Laboratory of Soft Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190, China.
At physiological or saturating ATP concentrations, some families of kinesin motors, such as kinesin-1 and kinesin-2, exhibit a predominant two-heads-bound (2HB) state during their stepping cycle on microtubules, while others, such as kinesin-3, exhibit a predominant one-head-bound (1HB) state. An interesting but unclear issue is what factors determine a kinesin motor in the predominant 1HB and 2HB states. Here, on the basis of the general chemomechanical pathway of the kinesin motors, a theory is given on fractions of 1HB and 2HB states.
View Article and Find Full Text PDFKIF1A, a neuron-specific Kinesin-3 motor, is indispensable for long-distance axonal transport and nuclear migration, processes vital for neuronal function. Using MINFLUX tracking, we reveal that KIF1A predominantly adopts a two-heads-bound state, even under ATP-limiting conditions, challenging prior models proposing a one-head-bound rate-limiting step. This two-heads-bound conformation, stabilized by interactions between the positively charged K-loop and negatively charged tubulin tails, enhances microtubule affinity and minimizes detachment.
View Article and Find Full Text PDFbioRxiv
March 2025
Department of Biomedical Engineering, Pennsylvania State University, University Park, Pennsylvania, USA.
Bidirectional cargo transport by kinesin and dynein is essential for cell viability and defects are linked to neurodegenerative diseases. Computational modeling suggests that the load-dependent off-rate is the strongest determinant of which motor 'wins' a kinesin-dynein tug-of-war, and optical tweezer experiments find that the load-dependent detachment sensitivity of transport kinesins is kinesin-3 > kinesin-2 > kinesin-1. However, in reconstituted kinesin-dynein pairs vitro, all three kinesin families compete nearly equally well against dynein.
View Article and Find Full Text PDFJ Virol
January 2025
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, New York, USA.
Unlabelled: Following reactivation of a latent alphaherpesvirus infection, viral particles are assembled in neuronal cell bodies, trafficked anterogradely within axons to nerve termini, and spread to adjacent epithelial cells. The virally encoded membrane proteins US9p and the glycoprotein heterodimer gE/gI of pseudorabies virus (PRV) and herpes simplex virus type 1 (HSV-1) play critical roles in anterograde spread, likely as a tripartite gE/gI-US9p complex. Two kinesin motors, kinesin-1 and kinesin-3, are implicated in the egress of these viruses, but how gE/gI-US9p coordinates their activities is poorly understood.
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