Cytoplasmic dynein-1 cargo diversity is mediated by the combinatorial assembly of FTS-Hook-FHIP complexes
- University of California, San Diego, United States
- Harvard University, United States
- University of Colorado Denver, United States
Abstract
In eukaryotic cells, intracellular components are organized by the microtubule motors cytoplasmic dynein-1 (dynein) and kinesins, which are linked to cargos via adaptor proteins. While ~40 kinesins transport cargo toward the plus end of microtubules, a single dynein moves cargo in the opposite direction. How dynein transports a wide variety of cargos remains an open question. The FTS-Hook-FHIP ('FHF') cargo adaptor complex links dynein to cargo in mammals and fungi. As human cells have three Hooks and four FHIP proteins, we hypothesized that the combinatorial assembly of different Hook and FHIP proteins could underlie dynein cargo diversity. Using proteomic approaches, we determine the protein 'interactome' of each FHIP protein. Live-cell imaging and biochemical approaches show that different FHF complexes associate with distinct motile cargos. These complexes also move with dynein and its cofactor dynactin in single-molecule in vitro reconstitution assays. Complexes composed of FTS, FHIP1B, and Hook1/Hook3 co-localize with Rab5-tagged early endosomes via a direct interaction between FHIP1B and GTP-bound Rab5. In contrast, complexes composed of FTS, FHIP2A and Hook2 colocalize with Rab1A-tagged ER-to-Golgi cargos and FHIP2A is involved in the motility of Rab1A tubules. Our findings suggest that combinatorial assembly of different FTS-Hook-FHIP complexes is one mechanism dynein uses to achieve cargo specificity.
Data availability
Supplementary files 1-3 contain all of the mass spectrometry data.
Article and author information
Author details
Jenna R Christensen
Adriana Aguilar-Maldonado
Samara L Reck-Peterson
Funding
Howard Hughes Medical Institute
- Samara L Reck-Peterson
National Institutes of Health (R01GM121772)
- Samara L Reck-Peterson
National Institutes of Health (R35GM141825)
- Samara L Reck-Peterson
National Institutes of Health (K99GM140269)
- Jenna R Christensen
American Cancer Society (PF-18-190-01-CCG)
- Agnieszka A Kendrick
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Andrew P Carter, MRC Laboratory of Molecular Biology, United Kingdom
Version history
- Preprint posted: October 8, 2021 (view preprint)
- Received: October 8, 2021
- Accepted: December 8, 2021
- Accepted Manuscript published: December 9, 2021 (version 1)
- Version of Record published: January 5, 2022 (version 2)
Copyright
© 2021, Christensen et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Cytoplasmic dynein-1 cargo diversity is mediated by the combinatorial assembly of FTS-Hook-FHIP complexes
eLife 10:e74538.
https://doi.org/10.7554/eLife.74538
