Portal de Periódicos da CAPES

Structure of human cytoplasmic dynein-2 primed for its power stroke

2014; Nature Portfolio; Volume: 518; Issue: 7539 Linguagem: Inglês

10.1038/nature14023

1476-4687

Helgo Schmidt, Ruta Zalyte, L. Urnavicius, Andrew P. Carter,

Protist diversity and phylogeny

The X-ray crystal structure of the human cytoplasmic dynein-2 motor bound to the ATP-hydrolysis transition state analogue ADP.vanadate is described. Dyneins are microtubule-associated motor proteins involved in a broad range of cellular processes, including flagellar motility and vesicular trafficking. Mutations in dynein-2 are associated with Jeune asphyxiating thoracic dystrophy and a developmental disorder known as primary ciliary dyskinesia. Here Helgo Schmidt et al. report the X-ray crystal structure of the human cytoplasmic dynein-2 motor bound to an ATP-hydrolysis transition state analogue. This structure — capturing the motor in a 'pre-power stroke' conformation — indicates that the closure of the six AAA+ domains drives the motor protein into a conformation that is primed to produce force. Members of the dynein family, consisting of cytoplasmic and axonemal isoforms, are motors that move towards the minus ends of microtubules. Cytoplasmic dynein-1 (dynein-1) plays roles in mitosis and cellular cargo transport1, and is implicated in viral infections2 and neurodegenerative diseases3. Cytoplasmic dynein-2 (dynein-2) performs intraflagellar transport4 and is associated with human skeletal ciliopathies5. Dyneins share a conserved motor domain that couples cycles of ATP hydrolysis with conformational changes to produce movement6,7,8,9. Here we present the crystal structure of the human cytoplasmic dynein-2 motor bound to the ATP-hydrolysis transition state analogue ADP.vanadate10. The structure reveals a closure of the motor’s ring of six AAA+ domains (ATPases associated with various cellular activites: AAA1–AAA6). This induces a steric clash with the linker, the key element for the generation of movement, driving it into a conformation that is primed to produce force. Ring closure also changes the interface between the stalk and buttress coiled-coil extensions of the motor domain. This drives helix sliding in the stalk which causes the microtubule binding domain at its tip to release from the microtubule. Our structure answers the key questions of how ATP hydrolysis leads to linker remodelling and microtubule affinity regulation.