7/26/2023 0 Comments Milton protein scaffold![]() ![]() Two mammalian Milton homologues are known, TRAK1 and TRAK2, (trafficking kinesin protein 1 and 2, respectively), with TRAK1 being the preferred binding partner of kinesin-1 42, 43. Mitochondria as cargo are physically linked to kinesin-1 by the adaptor proteins Miro and Milton 38, 39, 40, 41. In absence of cargo, kinesin-1 is auto-inhibited via an interaction of the cargo-binding domain with the motor domain 35, 36, 37. To enable robust long-range kinesin-1-driven transport in cells, additional mechanisms, complementary to the coupling of multiple molecular motors, are thus likely required to overcome the hindering effect of crowding on the microtubule surface.īinding of cargo, such as mitochondria, is mediated by adaptor proteins interacting with the C-terminal tail domain of kinesin-1. One of the key regulators of microtubule-based trafficking in neurons, the intrinsically disordered protein tau 29, 30, 31, can form densely crowded cohesive islands on microtubules, which strongly impede kinesin-1 motility 32, 33, 34. In vitro experiments demonstrate that crowding strongly impedes kinesin-1-driven transport through a drastic reduction of kinesin-1 processivity 25, 26, 27, 28. In the cytoplasm of living cells, however, microtubules are heavily decorated by a large variety of proteins, crowding the microtubule surface 24. Indeed, in living cells, various cellular cargoes are transported by multiple molecular motors 21, 22, 23. Reconstitutions of kinesin-1 stepping demonstrate that the coupling of multiple molecular motors to a single cargo increases cargo processivity 17, 18, 19, 20. Kinesin-1 is moderately processive in absence of other proteins on the microtubule surface in vitro, meaning that it can perform about 100 consecutive steps towards the microtubule plus-end, covering hundreds of nanometres before dissociating from the microtubule 16. Thus, kinesin-1 drives anterograde axonal transport 12, 13, 14 of mitochondria, which in vivo are transported in bursts of motion, covering distances of tens of micrometres 15. By hydrolysing ATP in its N-terminal motor domains, kinesin-1 heavy chain (further referred to as kinesin-1) moves in steps towards the plus-end of microtubules. Trafficking of cargo, including mitochondria, is driven by molecular motors such as kinesin-1 11. Active mitochondrial transport is equally essential for the redistribution of mitochondria during mitosis 4, 5 and trafficking of mitochondria between cells through tunnelling nanotubes 6, 7, 8 is relevant in tumour initiation and progression 7, 9, 10. Dysfunctions in the distribution of mitochondria are connected with neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease or amyotrophic lateral sclerosis 1, 2, 3. Microtubule-based transport is particularly important in neurons, where it enables an efficient distribution of cargo, such as mitochondria, along elongated axons to distal regions of the cell. In eukaryotic cells, microtubules constitute a major part of the cytoskeleton and provide a multi-functional scaffold crucial for intracellular long-range transport. We propose adaptor-mediated tethering as a mechanism regulating kinesin-1 motility in various cellular environments. Furthermore, TRAK1 enables mitochondrial transport in vitro. We explain the enhanced motility by the observed direct interaction of TRAK1 with microtubules, providing an additional anchor for the kinesin-1-TRAK1 complex. Interaction with TRAK1 i) facilitates kinesin-1 navigation around obstacles, ii) increases the probability of kinesin-1 passing through cohesive islands of tau and iii) increases the run length of kinesin-1 in cell lysate. Here, we demonstrate that TRAK1 (Milton), an adaptor protein essential for mitochondrial trafficking, activates kinesin-1 and increases robustness of kinesin-1 stepping on crowded microtubule surfaces. It is thus unclear how kinesin-1 acts as an efficient transporter in intracellular environments. Under crowding conditions, however, kinesin-1 motility is drastically impeded. In absence of other proteins on the microtubule surface, kinesin-1 performs micron-long runs. Intracellular trafficking of organelles, driven by kinesin-1 stepping along microtubules, underpins essential cellular processes. ![]()
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