RT Journal Article SR Electronic T1 Molecular mechanism for recognition of the cargo adapter Rab6GTP by the dynein adapter BicD2 JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202302430 DO 10.26508/lsa.202302430 VO 7 IS 7 A1 Zhao, Xiaoxin A1 Quintremil, Sebastian A1 Rodriguez Castro, Estrella D A1 Cui, Heying A1 Moraga, David A1 Wang, Tingyao A1 Vallee, Richard B A1 Solmaz, Sozanne R YR 2024 UL https://www.life-science-alliance.org/content/7/7/e202302430.abstract AB Rab6 is a key modulator of protein secretion. The dynein adapter Bicaudal D2 (BicD2) recruits the motors cytoplasmic dynein and kinesin-1 to Rab6GTP-positive vesicles for transport; however, it is unknown how BicD2 recognizes Rab6. Here, we establish a structural model for recognition of Rab6GTP 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 Rab6GTP that abolish binding to BicD2 also result in reduced co-migration of Rab6GTP/BicD2 in cells, validating our model. These mutations also severely diminished the motility of Rab6-positive vesicles in cells, highlighting the importance of the Rab6GTP/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.This study includes no data deposited in external repositories.