One
of the most important structures in a cell is the nuclear pore complex—a tiny
yet complicated channel through which information flows in and out of the
cell’s nucleus, directing all other cell activity.
Little
is known about this vital cell structure, but Massachusetts Institute of Technology (MIT)
biologist Thomas Schwartz is trying to change that. Using X-ray
crystallography, he is steadily assembling a thorough portrait of the 500
proteins that make up nuclear pores, and how they come together to perform
their crucial role.
“Nuclear
transport is fundamental to life,” Schwartz says. “If you want to understand
how a cell works, you need to understand how transport works.”
A
cell’s nucleus is where all of its genetic material is stored in the form of
DNA. Those genetic instructions are copied into messenger RNA, strands of which
have to exit the nucleus so they can direct the cell’s protein synthesis.
Proteins and other signaling molecules also pass through the nuclear pores.
However, many questions remain unanswered about how the pores are assembled,
and how they control so much activity.
“We
don’t know how proteins that reside in the nuclear membrane actually get there.
We don’t understand how viruses interact with the pore and how they go through.
And we don’t understand how such an enormous spectrum of substrates can go
through the same pore,” Schwartz says.
A complex task
Painstakingly piecing together the intricate interactions of the 500 proteins
in the nuclear pore complex is a task well suited to the analytical Schwartz.
Born in Stuttgart, Germany, Schwartz grew up
surrounded by “people who think analytically,” he recalls. Stuttgart
is home to many of Germany’s
automobile manufacturers, and Schwartz’s father was an automotive engineer at
Bosch, a company that makes fuel injection pumps. His mother also worked at
Bosch; his brother grew up to become a software engineer.
“I
was the odd one because I went into biology and chemistry. I was not really
that much into physics. I liked chemical explosions when I was a kid,” says
Schwartz, who earned tenure at MIT last June.
He
studied biochemistry at Berlin’s Freie University,
arriving on the day of German reunification in October 1990. After earning his
bachelor’s degree, he continued at Freie for his PhD but spent three years as a
visiting student at MIT, in the laboratory of legendary structural biologist Alexander
Rich.
Working
with Rich, who is best known for discovering the structures of left-handed DNA
and transfer RNA, was “inspirational,” Schwartz says. “Freie University
was a big university with lots of students and there wasn’t this personal touch
that is so normal at MIT. Here, somebody will really care about what you are
doing.”
In
Rich’s laboratory, Schwartz used X-ray crystallography to figure out the
structure of a protein that binds to left-handed DNA. X-ray crystallography—a
way to image molecules by bombarding them with X-rays—appealed to him more than
other scientific techniques, because “it’s a direct visual readout of a
molecule’s function,” he says. That makes it easier to get a clear answer,
instead of relying on data open to multiple interpretations.
After
earning his PhD, Schwartz went back to Berlin
for a year as a postdoc. However, he found that he missed the atmosphere at
MIT. “People here essentially live science, so if that’s attractive to you,
it’s hard to go anywhere else,” he says.
A fascinating structure
Schwartz decided to leave Berlin and did four
years of postdoctoral work at Rockefeller
University, where he
continued his research in X-ray crystallography. Working with Günter Blobel, he
became interested in the nuclear pore complex.
Around
this time, protein purification techniques and computational tools greatly
improved, making X-ray crystallography more accessible to more biology laboratories.
Blobel’s laboratory at Rockefeller, which focused on cell biology, had recently
started using X-ray crystallography to study how proteins are transported
across membranes. Schwartz focused specifically on transport through the
nuclear pore complex.
There
are 30 different types of proteins found in each pore; each pore contains a
total of about 500 protein molecules. “When you look at it from a structural
perspective, it’s one of the most fascinating and largest assemblies that we
know of in the cell,” Schwartz says.
At
MIT, Schwartz and members of his laboratory are piecing together the structure
of the pore by crystallizing a few of the proteins at a time, then combining
the structures of overlapping sections.
Learning
more about how nuclear pores work could help researchers come up with new ways
to block retroviruses, such as HIV, that enter the cell’s nucleus and take over
its genetic machinery.
“Any
retrovirus needs to go through the pore,” Schwartz says. “If you really
understood all the molecular interactions that happen there, you would have a
totally new avenue for generating drugs. There’s not a single drug at this
point that targets this process.”
