Molecular mechanism for recognition of the cargo adapter Rab6 GTP by the dynein adapter BicD2

• Published in: Life science alliance 2024-07, Vol.7 (7), p.e202302430
• Main Authors: Zhao, Xiaoxin, Quintremil, Sebastian, Rodriguez Castro, Estrella D, Cui, Heying, Moraga, David, Wang, Tingyao, Vallee, Richard B, Solmaz, Sozanne R
• Format: Article
• Language: English
• Subjects: Binding Sites; Dyneins - chemistry; Dyneins - metabolism; Guanosine Triphosphate - metabolism; Humans; Kinesins - chemistry; Kinesins - genetics; Kinesins - metabolism; Microtubule-Associated Proteins - chemistry; Microtubule-Associated Proteins - metabolism; Models, Molecular; Mutation; Protein Binding; Protein Transport; rab GTP-Binding Proteins - genetics; rab GTP-Binding Proteins - metabolism
• ISSN: 2575-1077; 2575-1077
• DOI: 10.26508/lsa.202302430

Rab6 is a key modulator of protein secretion. The dynein adapter Bicaudal D2 (BicD2) recruits the motors cytoplasmic dynein and kinesin-1 to Rab6 -positive vesicles for transport; however, it is unknown how BicD2 recognizes Rab6. Here, we establish a structural model for recognition of Rab6 by BicD2, using structure prediction and mutagenesis. The binding site of BicD2 spans two regions of Rab6 that undergo structural changes upon the transition from the GDP- to GTP-bound state, and several hydrophobic interface residues are rearranged, explaining the increased affinity of the active GTP-bound state. Mutations of Rab6 that abolish binding to BicD2 also result in reduced co-migration of Rab6 /BicD2 in cells, validating our model. These mutations also severely diminished the motility of Rab6-positive vesicles in cells, highlighting the importance of the Rab6 /BicD2 interaction for overall motility of the multi-motor complex that contains both kinesin-1 and dynein. Our results provide insights into trafficking of secretory and Golgi-derived vesicles and will help devise therapies for diseases caused by BicD2 mutations, which selectively affect the affinity to Rab6 and other cargoes.