What's Behind Cellular Morphing?
Bloom Gives IOM Crash Course on Public Health
Boning Up on Diversity
Rare Books Settle into New Quarters
New Vaccine Works Better Using Infection-Specific Antigen
Nerve Regrowth Suggests New Research, Therapies
Collaring Suspect Protease Slows HuntingtonŐs in Mice
Toy Muscles Linked To Harmful Image of Male Body
Taming T Cells May Enlarge the Bone Marrow Donor Pool
Faculty Council Hears On-line Issues
Fourth Annual A. Clifford Barger Lecture
Faculty Awards for Excellence in Teaching
Honors and Advances
Future Discussed, Past Honored in Affirmative Action Program
Minority Grads Have Aspired to Give More than Good Medicine
Collaboration Sheds Light on Assembly Of Cellular
Continuing their work on the structure of clathrin, Tomas Kirchhausen,
HMS professor of cell biology at the Center for Blood Research;
Stephen Harrison, HMS professor of biological chemistry and
molecular pharmacology at Children's Hospital and the Howard Hughes
Medical Institute; and Andrea Musacchio, a former postdoctoral
fellow in Harrison's lab, have developed a newly detailed view of
clathrin-coated vesicles, one of the best understood cellular import
machines. Responsible for shuttling into the cell a range of important
molecules including LDL cholesterol, clathrin-coated vesicles also
play a role in breast cancer through internalization of a key receptor.
Their findings, presented in the June Molecular Cell, combine
X-ray crystallography data of the clathrin molecule, at 2.6 angstroms,
with the cryo-electron microscope view of a clathrin cage, at 21
angstroms, from collaborators in England.
Clathrin, a three-legged pinwheel molecule, forms
a lattice of hexagons and pentagons like a soccer ball around the
vesicle. The lattice forms with the help of adaptor proteins, making
coated pits that grow and pinch off, internalizing receptors on
the cell membrane.
After fitting the X-ray data into the electron
microscope data, the researchers found that the image of an individual
clathrin molecule, or triskelion, is highly puckered, almost resembling
an upside-down teacup. It is also a relatively rigid molecule, though
there is some amount of flex at the "knees."
To reconcile the rigidity of the individual triskelion
with the tightly packed and complicated structure of the coated
vesicle, the researchers propose that during assembly and disassembly,
the triskelion rotates to lock into position (see image).
The combined structures also gave them a view
of the "feet" of clathrin showing that these domains, which bind
adaptor proteins and receptors, project into the vesicle at the
perfect depth to interact with their cargo.
A Web movie of the vesicle's assembly appears
Brief by Justin Yarrow
Human Circadian Clock Shown
To Keep 24-Hour Time
Our internal clocks are more in sync with our wristwatches than
previously believedthat's the finding of a team of Brigham
and Women's circadian biologists. Charles Czeisler, Jeanne Duffy,
Derk-Jan Dijk, and their colleagues have recently discovered
that the human circadian pacemakerthe internal clock that
controls the rise and fall of body temperature, cortisol, and hormones
such as melatonincycles, on average, every 24.18 hours. The
finding, which appears in the June 25 Science, settles a longstanding
Plants, insects, mammals, and other animals were
known to cycle on a near 24-hour basis, with little variation between
individuals. Experiments with humans, on the other hand, suggested
that they had a longer average cycle, over 25 hours, and that their
cycles could vary anywhere from 13 to 65 hours.
The experiments suffered from a serious flaw,
however. Subjects were allowed to turn on lights, even if they were
tucked away in caves or windowless labs. Several years ago, Czeisler
and his colleagues discovered that ordinary room light can reset
To avoid the resetting effects of room light
and other cues, Czeisler, professor of medicine; Duffy, research
fellow in medicine; and Dijk, assistant professor of medicine; and
their colleagues tightly controlled their subjects' environment.
For about a month, the 24 subjects11 young men (mean age 24)
and 13 older men and women (mean age 67)were exposed only
to very low levels of light, about one tenth that of ordinary room
light. To prevent the pattern of light exposure from affecting the
subjects' internal clocks, lights were turned on at progressively
earlier or progressively later times of the day, essentially creating
20-hour or 28-hour days.
"The point was to decouple extrinsic cues from
the internal pacemaker," says Czeisler. Despite the decoupling,
body temperature, cortisol, and melatonin levels cycled on an average
of every 24.18 hours. And they did so consistently among all subjects,
showing the circadian pacemaker is as tightly controlled in humans
as in other animals.
The discovery has implications for our understanding
not just of sleep disorders, some of which have been attributed
to instabilities in the circadian pacemaker, but of the human circadian
clock itself. "It's very likely the breakthroughs over the past
one to two years regarding the molecular basis of circadian rhythms
in other animals apply to human beings as well," says Czeisler.
Housekeeping Receptor in Fruit Flies Found
When they are not busy fending off foreign invaders, macrophages,
the workhorses of the immune system, are responsible for cleaning
up debris such as dead cells. Until recently, little was known about
how macrophages perform their housekeeping duties in fruit flies.
A team of Massachusetts General Hospital researchers has identified
the macrophage receptor that is responsible for recognizing apoptotic
cells in Drosophila embryos. The receptor, dubbed croquemort (CRQ),
is related to a receptor found on mammalian macrophages that is
known to recognize dead, or apoptotic, cells.
In fact, the homology to the mammalian CD36 receptor
was the first tip that CRQ might be involved in engulfing apoptotic
cells. To test the hypothesis, Nathalie Franc, research fellow
in dermatology, Kristin White, assistant professor of dermatology,
and their colleagues deleted a region of the fly genome that contains
the crq gene. Fly embryos were littered with cellular corpses. They
tried rescuing flies by reintroducing the crq gene, and the trick
worked. "Macrophages were competent to engulf corpses," says White.
Moreover, the presence of apoptotic cells appeared to upregulate
the CRQ receptor, the researchers report in the June 18 Science.
Intriguingly, flies lacking the crq gene were
still able to engulf foreign invaders, such as bacteria. This suggests
that macrophages use two different pathways to recognize apoptotic
cells and bacteria. The researchers plan to study what surface feature
macrophages use to recognize apoptotic cells.
"This is the first engulfment mutant in flies,"
White says. "It shows flies will be a good model system to study
engulfment by professional macrophages."