TY - JOUR TI - Cytoplasmic dynein-1 cargo diversity is mediated by the combinatorial assembly of FTS–Hook–FHIP complexes AU - Christensen, Jenna R AU - Kendrick, Agnieszka A AU - Truong, Joey B AU - Aguilar-Maldonado, Adriana AU - Adani, Vinit AU - Dzieciatkowska, Monika AU - Reck-Peterson, Samara L A2 - Carter, Andrew P A2 - Akhmanova, Anna A2 - Carter, Andrew P VL - 10 PY - 2021 DA - 2021/12/09 SP - e74538 C1 - eLife 2021;10:e74538 DO - 10.7554/eLife.74538 UR - https://doi.org/10.7554/eLife.74538 AB - 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 humans 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 colocalize 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. KW - dynein KW - dynactin KW - endosome KW - microtubule KW - Rab5 KW - Rab1 JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -