ASCB Newsletter Nov 2013 - page 8

Answering some fundamental questions in
biology requires an interdisciplinary approach
in which cell biologists, biochemists, and
physicists combine forces. Our recent paper
on stacked endoplasmic reticulum (ER) sheets
is an excellent example of the success of such
a collaboration.
The paper would not have
been possible without
people of diverse
expertise coming
together and making
essential experimental
and theoretical
Questions about
Scientists have
been fascinated with biological shapes and
structures for centuries. However, much
of the analysis has remained descriptive,
and fundamental questions about how
morphologies are generated have remained
unanswered. Intracellular organelles offer one
system in which we have a realistic chance to
understand on a molecular level how shapes are
formed. And of those, the ER is particularly
intriguing and accessible to investigation. It is
a continuous membrane system, composed of
sheets and a network of tubules. What are the
molecules that shape these tubules and sheets?
What are the physical principles behind the
observed morphologies?
Our recent work built on earlier studies
that addressed how the reticular ER network
is formed (for reviews, see references 2 and
3). These studies identified two protein
families that shape tubules, the reticulons and
and other proteins, including
the atlastins, that fuse the tubules into a
Importantly, it turned out that
the reticulons and DP1/Yop1p form tubules
by stabilizing the high membrane curvature
of the cross-section. The same fundamental
principle allows these proteins to generate
sheets, because they can stabilize the curvature
of sheet edges and thereby keep the two flat
membranes of a sheet closely apposed.
Connecting Sheets
Our paper deals with another striking ER
morphology: stacked ER sheets. Their discovery
goes back more than 60 years, when Keith
Porter first used thin-sectioning electron
microscopy on tissues. Subsequently, George
Palade, Don Fawcett,
and others obtained
pictures of stacked
rough ER membranes in
“professional” secretory
cells such as pancreatic
and salivary gland cells.
In these cells, many
membrane sheets, densely
covered with membrane-
bound ribosomes, are
stacked on top of each
other in a strikingly regular manner. Those
amazing images have made it into every
textbook of cell biology, but surprisingly,
nobody had bothered to ask how the sheets are
Analyzing the sheet connections required
new electron microscopy methods. Luckily,
Jeff Lichtman’s group at Harvard had recently
developed an improved ultra-thin sectioning
technique. Using a staining protocol that
accentuates membranes and a device in which
consecutive sections are automatically fed
into a scanning electron microscope, they
obtained unprecedented resolution. The results
were surprising: The stacked ER sheets of a
professional secretory cell turned out to be a
continuous membrane system, in which the
sheets are connected by twisted membrane
surfaces. The structure resembles a parking
garage, where the different levels are connected
by helicoidal ramps. As one might expect, the
helical edges of the connecting membrane
surfaces are either left- or right-handed. The
structure is immediately appealing, because it
allows the dense packing of ER sheets in the
restricted space of a cell. In addition, ribosomes
can move around in the continuous membrane
system and the nearly flat surfaces allow even
large polysomes to bind. (Membrane stacking
is quite different in the Golgi; there the sheets
Interdisciplinary Collaboration Reveals a
New Twist on the Endoplasmic Reticulum
Mark Terasaki
Tom Rapoport
Vantage Point is
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ASCB members
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