TY - JOUR TI - Lis1 regulates dynein by sterically blocking its mechanochemical cycle AU - Toropova, Katerina AU - Zou, Sirui AU - Roberts, Anthony J AU - Redwine, William B AU - Goodman, Brian S AU - Reck-Peterson, Samara L AU - Leschziner, Andres E A2 - Kuriyan, John VL - 3 PY - 2014 DA - 2014/11/07 SP - e03372 C1 - eLife 2014;3:e03372 DO - 10.7554/eLife.03372 UR - https://doi.org/10.7554/eLife.03372 AB - Regulation of cytoplasmic dynein's motor activity is essential for diverse eukaryotic functions, including cell division, intracellular transport, and brain development. The dynein regulator Lis1 is known to keep dynein bound to microtubules; however, how this is accomplished mechanistically remains unknown. We have used three-dimensional electron microscopy, single-molecule imaging, biochemistry, and in vivo assays to help establish this mechanism. The three-dimensional structure of the dynein–Lis1 complex shows that binding of Lis1 to dynein's AAA+ ring sterically prevents dynein's main mechanical element, the ‘linker’, from completing its normal conformational cycle. Single-molecule experiments show that eliminating this block by shortening the linker to a point where it can physically bypass Lis1 renders single dynein motors insensitive to regulation by Lis1. Our data reveal that Lis1 keeps dynein in a persistent microtubule-bound state by directly blocking the progression of its mechanochemical cycle. KW - dynein KW - electron microscopy KW - Lis1 KW - microtubules KW - structure JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -