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Tatyana Polenova (second from left) with her UD research team (from left), Xingyu Lu, Changmiao Gao, Huilan Zhang and Guangjin Hou.
A latticework of tiny tubes called
microtubules gives your cells their shape and also acts like a railroad
track that essential proteins travel on. But if there is a glitch in the
connection between train and track, diseases can occur.
In the Proceedings of the National Academy of Sciences,
Tatyana Polenova, professor of chemistry and biochemistry, and her team
at the University of Delaware, together with John C. Williams,
associate professor at the Beckman Research Institute of City of Hope in
Duarte, California, reveal for the first time atom by atom the
structure of one of these proteins bound to a microtubule.
The protein of focus, CAP-Gly, short for cytoskeleton-associated
protein-glycine-rich domains, is a component of dynactin, which binds
with the motor protein dynein to move cargoes of essential proteins
along the microtubule tracks. Mutations in CAP-Gly have been linked to
such neurological diseases and disorders as Perry syndrome and distal
spinal bulbar muscular dystrophy.
The research team used magic-angle-spinning nuclear magnetic resonance spectrometry (NMR) in the Department of Chemistry and Biochemistry
at UD to unveil the structure of the CAP-Gly protein assembled on
polymerized microtubules. The CAP-Gly protein has 1,329 atoms, and each
tubulin dimer, which is a building block for microtubules, has nearly
This is the first time anyone has been able to get an
atomic-resolution structure of any microtubule-associated protein
assembled on polymerized microtubules, Polenova says. With
magic-angle-spinning NMR, we can look into the structure of this and
other assemblies of microtubules and their associated proteins and gain
critical insights into their function and dynamics, as well as begin to
gather clues as to how mutations cause disease.
In this technique, a sample is placed in the NMRs small, tube-like
rotor, which is then spun inside the NMR magnet at an angle of 54.74
degrees called the magic angle because it suppresses the atoms from
The result is a high-resolution protein fingerprint, a graph of
hundreds of peaks representing the frequencies of two or more
interacting atoms. These data are then used to calculate the 3-D
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An example of one MAS NMR spectrum. This is used to identify atoms in the molecule and, ultimately, for calculating their 3-D structures.
The 3-D structures of CAP-Gly, which show the spatial arrangement of
atoms in the protein molecule, are different between the free state of
the protein and its bound state to the microtubule. These structures
reveal how the protein interacts with microtubules, predominantly
through its loop regions, which adopt specific conformations upon
However, static structures of CAP-Gly do not tell the whole story about the protein.
Just as we are always moving our arms and legs about, proteins are
very dynamic. They do not stand still, Polenova says. These motions
are essential to their biological function, and NMR spectroscopy is the
only technique that can record such movements, with atomic resolution,
on a variety of time scales, from picoseconds to arbitrarily long time
scales seconds, days, weeks to help us understand the proteins
function. We know from our prior studies that CAP-Gly is dynamic on
timescales from nano- to milliseconds, and this mobility is essential
for the proteins ability to interact with microtubules and with
multiple other binding partners.
The research, which has been ongoing since 2008 when the first data
sets were collected, required the development of new protocols for
preparing the samples, new NMR experiments to gather various information
on structure and dynamics, and new protocols for data analysis.
In the future, Polenova and her team envision using NMR in
combination with cryo-electron microscopy, in which samples are studied
at extremely low temperatures, typically below 200 degrees Fahrenheit,
to look at even more complex systems in a highly preserved form.
Polenovas research team at UD included Si Yan, who received her
doctorate from the University in 2014, current doctoral student
Changmiao Guo, NMR spectroscopist Guangjin Hou and postdoctoral
researchers Huilan Zhang and Xingyu Lu. Williams, at Beckman Research
Institute, also was a co-author of the study.
The research was supported by the National Institutes of Health
through a grant from the National Institute of General Medical Sciences.
The National Science Foundation funded one of the NMR spectrometers used in the research.
Polenova and her students and colleagues published a second article,
on protein regulation of HIV activity, in the same issue of the Proceedings of the National Academy of Sciences. Read that UDaily article here.