Research Spotlight
Dr. James McNew
 

A few years ago Dr. James McNew, Rice University Associate Professor of Biochemistry and Cell Biology, and his lab were studying SNARE proteins and their function in membrane fusion.  He was contacted by a collaborator who thought his expertise in membranes might be helpful in looking at another protein, atlastin, a GTPase found in the endoplasmic reticulum (ER).  After changing the focus of his lab to this new pursuit, McNew’s gamble was rewarded with a 4 year R01 grant from the National Institutes of Health.

Atlastin mutations have been implicated in hereditary spastic paraplegia (HSP), a motor neuron disorder in which affected patients experience increasing lower-extremity weakness and spasticity.  In more than half the cases, the physical symptoms are associated with mutations in endoplasmic reticulum (ER) related proteins.  The prevailing hypothesis is that improper ER function leads motor neuron loss and onset of physical symptoms.  Localized to tubular ER, atlastin associates with other proteins involved with tubule formation.  When atlastin function is lost, either through mutations to the GTP binding region or other domains, ER tubule formation is affected, resulting in the disease state.

While atlastin was known to be a GTPase, McNew’s lab was the first to demonstrate that the enzymatic activity is coupled with membrane fusion.  Through a  subsequent series of elegant domain mapping experiments done using recombinant atlastin protein made in their lab, the McNew group was able to assign specific roles of the membrane fusion process to different domains of atlastin.   

In the McNew model, supported by X-ray crystallography by other groups, atlastin molecules first bind nucleotides with the N-terminus domain and dimerize.  Hydrolyzing the GTP may provide the energy required for the conformational change, twisting the middle domains of the atlastin dimer together and positioning the C-terminus tail against the membrane surface.  The C-terminus tail interacts with the membranes and drives the fusion of the separate membranes.  As the membranes fuse, the GDP molecule is released, allowing the pair to separate and migrate away.

The BioScience Research Collaborative (BRC) strongly encourages partnerships in research, and recognizes the McNew lab not only for their outstanding research but also for their collaboration with Dr. Michael Stern as they transitioned from a Saccharomyces cerevisiae lab to a new model system, Drosophila melanogaster.

References

Orso G, et al. (2009) Homotypic fusion of ER membranes requires the dynamin-like GTPase Atlastin. Nature 460:978–983.

Moss T, et al. (2011) Membrane fusion by the GTPase atlastin requires a conserved C-terminal cytoplasmic tail and dimerization through the middle domain. PNAS 108:11133-11138

Byrnes, et al. (2011) Structural basis for the nucleotide-dependent dimerization of the large G protein atlastin-1/SPG3A. PNAS 108:2216-2221.

Moss T, et al. (2011) Fusing a lasting relationship between ER tubules.  Trends in Cell Biology, 21:416-423.

Pendin D, et al. (2011) Balancing ER dynamics: shaping, bending, severing and mending membranes.  Current Opinion in Cell Biol, 23:435-442.