Transporting cargo over long distances: insights from dynein/dynactin structure
Andrew Carter, MRC Laboratory of Molecular Biology, Cambridge, UK
Cells depend on components being moved to the correct place at the correct time. My group is interested in cytoplasmic dynein-1 (dynein), a motor which delivers many different cargos via the microtubule network. When dynein is mutated it leads to neurodegeneration and it is susceptible to hijack by viruses which use it to travel into the cell. In the presence of cargo adaptor proteins, such as BICD, dynein binds a cofactor called dynactin. This generates a transporter complex capable of long distance movement along microtubules. We have used cryo-electron microscopy (cryo-EM) to determine a 4.0Å structure of dynactin that explains how this 23 subunit complex is assembled. We subsequently used cryo-EM, in vitro motility assays and in cell assays to determine why dynein is inhibited when it is on its own and how it is activated by binding dynactin. We are now working to understand how the cargo adaptors specifically recruit dynein to dynactin.
Articles on this subject, published by the speaker can be found at Pubmed.
I became interested in structural biology as an undergraduate at the University of Oxford. This led me to start a PhD in 1999 with Venki Ramakrishnan at the MRC Laboratory of Molecular Biology in Cambridge. I worked as part of the team that determined the X-ray crystal structure of the small (30S) ribosomal subunit. In addition I solved structures of the ribosome bound to antibiotics and the protein initiation factor IF1. After my PhD I spent an extra year in Cambridge as a junior research fellow at Clare College, before moving in 2003 to Ron Vale's lab at the University of California where I started working on dynein. Together with Sam Reck Peterson I used S.cerevisiae to express a recombinant dynein motor for biophysical studies (2006). I collaborated with the group of Ian Gibbons to solve the structure of dynein's microtubule binding domain (2008) and together with Carol Cho produced the first crystal structure of the dynein motor domain (2010). In 2008 I accepted a group leader position back at the MRC-LMB which I started in August 2010. My group pushed the yeast motor domain structure to high resolution (2012). We subsequently solved the structure of a human dynein motor domain (dynein-2) bound to the transition state analog ADP.vanadate (2014), which revealed how ATP hydrolysis drives the conformational changes in dynein that generate movement. In 2015 we published used cryo electron microscopy to determine the structure of the dynactin complex and how it bound to dynein.