Decades-old structural mystery surrounding the birth of energy-storing
lipid droplets solved

Date:
February 25, 2022
Source:
UT Southwestern Medical Center
Summary:
In humans, virtually every cell stores fat. However, patients
with a rare condition called congenital lipodystrophy, which is
often diagnosed in childhood, cannot properly store fat, which
accumulates in the body's organs and increases the risk of early
death from heart or liver disease.

In 2001, a transmembrane protein called seipin was identified as a
molecule essential for proper fat storage, although its mechanism
has remained unknown.



FULL STORY ==========================================================================
In humans, virtually every cell stores fat. However, patients with
a rare condition called congenital lipodystrophy, which is often
diagnosed in childhood, cannot properly store fat, which accumulates
in the body's organs and increases the risk of early death from heart
or liver disease. In 2001, a transmembrane protein called seipin was
identified as a molecule essential for proper fat storage, although its mechanism has remained unknown.


==========================================================================
An international study published in Nature Structural & Molecular Biology
is the first to solve and model virtually the entire structure of seipin, revealing it exists in two conformations and pointing to the mechanism
for birthing the lipid droplets used for fat storage in healthy cells.

"Lipid droplets (LDs) have been described since the invention of
microscopes that could show the inside of cells. For about a century,
they've been known to store lipids, or fats, but they were considered
inactive. During the past 20 years, lipid droplets have been shown to
be very dynamic," said Joel M.

Goodman, Ph.D., Professor of Pharmacology at UT Southwestern,
a Distinguished Teaching Professor, and one of the study's three
corresponding authors.

Dr. Goodman has played a key role in seipin biology, discovering in 2007
that seipin is responsible for packaging fat into LDs and that the same mechanism occurs in animals, plants, and fungi. In 2010, the Goodman
lab was the first to purify seipin and reported that it was composed of
about nine identical subunits that resembled a donut.

Ever since, scientists around the world had tried to solve the
structure, which proved very difficult because seipin stretches across
the membrane of the endoplasmic reticulum, an organelle within the
cell. That transmembrane placement made the complex resistant to X-ray crystallography, the longtime gold standard for such studies. Membrane
proteins are notoriously difficult to crystallize, a requirement for
that technique.

To tackle the problem, Dr. Goodman turned to cryogenic electron microscopy (cryo-EM) after discussions with Boston cell biologist Tobias C. Walther, Ph.D., at a scientific conference. Dr. Walther, a Howard Hughes Medical Institute Investigator, and his colleague, Robert V. Farese Jr., M.D.,
are the study's other corresponding authors. They both have appointments
at Harvard Medical School, the T.H. Chan School of Public Health,
and the Broad Institute of MIT and Harvard. The study used the Harvard
cryo-EM facility.

Cryo-EM uses flash-frozen samples, electron beams, and an electron
detector rather than a camera to gather data on biological structures at near-atomic scale. Using cryo-EM enabled the researchers to determine
that the "donut" they hypothesized was actually a 10-unit cage, a sort
of incubator to create and grow lipid droplets. The second conformation
showed seipin opening to release the lipid droplet onto the surface of
the endoplasmic reticulum. Once on the surface, the LDs face the cell's
soupy interior (the cytoplasm), where passing enzymes can break down
the LDs and free the fatty acids inside to provide energy such as during
times of starvation, Dr. Goodman said.

"Getting two conformations was amazing, totally unexpected," Dr. Goodman
said, adding that previously other research teams had gotten a partial
solution showing the lower layer of the seipin complex contained within
the tube-like endoplasmic reticulum. The two conformations in the
current investigation solve the elusive upper part of the structure,
which extends across the organelle's membrane.

"Cryo-EM made it possible," Dr. Goodman said. "We hope that this structure
will lead to a way of connecting seipin's role in lipid-droplet creation
to whatever goes wrong in lipodystrophy as well as help us better
understand lipid-droplet formation in general," he added. "There are
likely several other proteins involved in the creation of lipid droplets,
but seipin appears to be the main one. It seems to be a machine that
generates lipid droplets." Current and former UTSW co-authors include
Brayden Folger and Xiao Chen. The lead author is Henning Arlt of Harvard
and HHMI. Researchers from the University of Washington, Seattle, and Heidelberg University, Germany, also participated.

The study received support from the National Institutes of Health
(R01GM124348, R01GM084210), the German Research Foundation, the American
Heart Association, and the HHMI.

Dr. Goodman holds the Jan and Bob Bullock Distinguished Chair for
Science Education.

========================================================================== Story Source: Materials provided by UT_Southwestern_Medical_Center. Note: Content may be edited for style and length.


========================================================================== Related Multimedia:
* Depiction_of_the_seipin_complex ========================================================================== Journal Reference:
1. Henning Arlt, Xuewu Sui, Brayden Folger, Carson Adams, Xiao Chen,
Roman
Remme, Fred A. Hamprecht, Frank DiMaio, Maofu Liao, Joel M. Goodman,
Robert V. Farese, Tobias C. Walther. Seipin forms a flexible cage
at lipid droplet formation sites. Nature Structural & Molecular
Biology, 2022; DOI: 10.1038/s41594-021-00718-y ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220225135646.htm

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