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
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
Orso G, et al. (2009) Homotypic fusion
of ER membranes requires the dynamin-like GTPase Atlastin. Nature 460:978–983.
T, et al. (2011) Membrane fusion by the GTPase atlastin requires a conserved
C-terminal cytoplasmic tail and dimerization through the middle domain. PNAS
Byrnes, et al. (2011) Structural basis for the
nucleotide-dependent dimerization of the large G protein atlastin-1/SPG3A. PNAS
T, et al. (2011) Fusing a lasting relationship between ER tubules. Trends in Cell Biology, 21:416-423.
D, et al. (2011) Balancing ER dynamics: shaping, bending, severing and mending
membranes. Current Opinion in Cell Biol,