Transcript Protein folding is essential to life

Protein folding is essential to life
Mad cow disease, or bovine
spongiform encephalopathy
(BSE), is a fatal brain disorder
that occurs in cattle. Abnormal
protein folding is considered
crucial to the onset of the
disease.
What causes mad cow?
To illustrate the concept of
protein folding we chose villin,
a protein which exists in the
stomach and intestine of
animals (including homo
sapiens).
Why do proteins fold?
Try protein folding!
More info
Credits
What causes mad cow?
In a bovine epidemic that struck the UK in 1986, 170,000 cows
appeared to be mad: they drooled and staggered, were extremely
nervous, or bizarrely aggressive. They all died. As the brains of the
dead “mad” cows resembled a sponge, the disease was called
bovine spongiform encephalopathy, or BSE.
Other examples of spongiform encephalopathy are scrapie which
develops in sheep, Creutzfeld-Jacob Disease (known as CJD) and
its variant form (known as vCJD) which develop in humans.
Dr. Prusiner, in 1982, identified the infectious agent responsible for
transmitting spongiform encephalopathy in “proteinaceous
infectious particles”, which he named prions.
Prions are proteins that are found in the nerve cells of all
mammals. Many abnormally-shaped prions are found in the brains
of BSE-infected cows and humans afflicted with vCJD or CJD.
The difference in normal and infectious prions may lie in the way
they fold.
Brain surface of CJD patient on autopsy
showing sponge-like appearance
How do prions fold?
Humans may be
infected by prions in
2 ways: 1 - acquiring
the infection through
an infecting agent
(through diet or as
the result of medical
procedures such as
surgery, injections of
growth hormone,
corneal transplants,
possibly blood
transfusion);
and 2 - hereditary
transmission.
How do proteins fold?
How do prions fold?
Evidence indicates that the infectious agent in
transmissible spongiform encephalopathy is a
protein. Stanley Prusiner pioneered the study of
these proteins and received the Nobel Prize in
1997. He has named them prion proteins (referred
to as PrP) or simply prions.
Proteins have primary structures, which is their
sequence of amino acids, and secondary
structures, which is the three dimensional shape
that one or more stretches of amino acids take.
The most common shapes are the alpha helix and
the beta conformation.
The normal protein is called PrPC (for cellular). Its
secondary structure is dominated by alpha helices.
The abnormal, disease producing protein called
PrPSc (for scrapie), has the same primary
structure as the normal protein, but its secondary
structure is dominated by beta conformations.
Examples of alpha helices
and beta sheets
The “kiss of death”
A person ingests an abnormally-shaped
prion from contaminated food or other
contaminated sources.
The abnormally-shaped prion gets
absorbed into the bloodstream and
crosses into the nervous system.
The abnormal prion touches a normal
prion and changes the normal prion's
shape into an abnormal one, thereby
destroying the normal prion's original
function.
Both abnormal prions then contact and
change the shapes of other normal
prions in the nerve cell.
The nerve cell tries to get rid of the
abnormal prions by clumping them
together in small sacs. Because the
nerve cells cannot digest the abnormal
prions, they accumulate in the sacs
that grow and engorge the nerve cell,
which eventually dies.
When the cell dies, the abnormal prions
are released to infect other cells.
Large, sponge-like holes are left where
many cells die.
Why do proteins fold?
Like all proteins, villin is formed by a unique sequences of aminoacids. However, only knowing the sequence tells us little about
what the protein villin does and how it does it.
In order to carry out their function (for instance as enzymes or
antibodies), proteins must take on a particular shape, also known
as a "fold." Thus, proteins are truly amazing machines: before they
do their work, they assemble themselves! This self-assembly is
called "folding."
Villin’s function is to give structure to intestinal villi, which are a
bundle of actin filaments. Intestinal villi augment the surface of the
intestine to increase food absorption. However intestinal villi need
to be “stabilized”, to add rigidity. Villin accomplishes this goal by
folding in a certain particular way in which it attaches to actin
(another protein) filaments at specific receptor point. One and only
one way of folding is the correct way.
Distributed dynamics simulate the complexity of the mechanisms of
protein folding, which happens extremely rapidly.
Forms determines function
Suppose you have some molten iron.
You may turn it into nails, hammers,
wrenches, etc. What makes these tools
different from each other is their form
(i.e. their shape and structure).
Distributed dynamics
Try protein folding!
Distributed dynamics
Distributed dynamics is like
processing something in parallel.
It means breaking down a large
task into smaller tasks and
assigning them simultaneously
(i.e. in parallel) to a number of
resources instead of assigning
them to one resource that can
get to each task one at the time.
The overall large task will thus be
completed faster.
Your local post office provides a
good analogy to distributed
dynamics. The one at the left
has only one window open. The
one at the light has three. To
which one would you rather go if
you are in a hurry?
you
How can you help?
Results from Folding@Home
simulations of villin
Length of time of
a certain event
Time it takes to simulate
event on computer
1 nanosecond =
1/1,000,000,000
seconds
1 day
1 microsecond =
1/1,000,000
seconds
1,000 days, almost 3
years
Typical protein
folding time
10,000 days, almost 30
years
Since October 1, 2000,
almost 1,000,000 CPUs
worldwide have
participated Dr. Pande’s
computational research
Folding@Home
Proteins fold, amazingly
quickly: some as fast as a
millionth of a second
(microsecond).
While this time is very fast
on a person's timescale, it's
remarkably long for
computers to simulate.
Dr. Pande at Stanford
University applied an
innovative computational
method and large scale
distributed computing
(called Folding@Home), to
simulate timescales
thousands to millions of
times longer than
previously achieved. This
has allowed him to
simulate folding for the first
time.
How can you help?
http://folding.stanford.edu/download.html
Everybody can help the
project by downloading the
necessary software at the
link shown at the side and
running our client software
on their computer.
For every computer that
joins the project, there is a
proportional increase in
simulation speed.
Download the software in
your classroom and make
your school be part of an
exciting cutting edge
research that can benefit
advancements in medicine
and biology.
Using the down time of your computer connected to the web
the Folding@Home client software shows real time
visualizations of the protein simulations being performed.
The molecule drawn is the current atomic configuration
("fold") of the protein being simulated on your computer.
Try protein folding!
The model shows how the villin
protein might look if you were able
to see it at the molecular level and
if each amino acid was kind enough
to be naturally color coded. Each
sphere represents an amino acid,
each different color represent each
type of amino acids (36 in total).
Villin has been heavily studied
experimentally and by simulation
since it is perhaps one of the
smallest, fastest folding proteins.
It has a hydrophobic (i.e. water
hating) core made of two
groups (phenylalanine - blue and
anotheralanine - gray), but also has
two groups (a tryptophan – light
orange and another lysine - green)
which are hydrophilic (i.e. water
loving).
For villin to correctly attach
T
to the
actin filaments it needs
to fold so that it can attach to
the receptor sites of the actin
filaments. We have simulated
this fast naturally occurring
process by means of
magnets, which are attached
to the villin protein and to the
actin filaments. While each
bend can fold in more than
one direction, you will have
to find the correct set of folds
for the two bend that are
show in the model for villin to
properly attach.
Go ahead and try. Are you
able to find the set of moves
that gives you a perfect
attachment?
Once you have succeeded,
you have simulated what
happens in our bodies
millions of times every day, in
million of possible
alternatives.
Teacher’s resources
Teacher’s resources
Are you a high school teacher of Chemistry or Biology? Are you interested in
teaching protein folding? A set of ready-to-use classroom resources, aligned
with California Science Standards, can be downloaded from the web.
General description of project components
To Fold or Not To Fold is an introduction to key terminology, the importance of protein folding, and Villin.
It is linked to the “Snack Presentation”, described below.
The Chemistry of Villin is a tiered introduction to protein structure using Villin as a specific protein. It is
linked to a lesson plan that asks students to compute the molar mass of Villin.
The Biology of Protein Folding includes detailed descriptions of the current mechanisms of protein
folding.
The Snack Presentation is an activity which allows students to build a simple model that exhibits
hydrogen bonding, using wood dowels and magnets.
The Lesson Plan requires students to compute the molar mass of Villin (Teacher and Student versions).
The Exploratorium Presentation is geared to educate the general public.
To Fold or
Not to Fold?
The Chemistry
of Villin
The Biology of
Protein Folding
Snack Presentation
Lesson Plan
Photo of Snack
Suggested reading and references
for teachers and students
Michael Crichton, Prey, Harper Collins, 2002
How the cows turned mad, Maxime Schwartz, University of California
Press, 2003
Jeremy Cherfas, The human genome, Dorling Kindersely, 2002
Mark Ratner & Daniel Ratner, Nanotechnology, Prentice Hall
http://www.wyfda.org/ member/cj_2.html
http://www.darlingii.com/rendering/procurement.htm
http://www-micro.msb.le.ac.uk/Tutorials/cow/cow1.html
http://www-micro.msb.le.ac.uk/3035/prions.html
Credits
CPIMA provided leadership
and vision.
Dr. Pande’s group provided
inspiration and research
material.
The Exploratorium in San
Francisco supported us in a
hands-on approach to
science and effective
science museum
communication philosophy
Dreyfus Foundation
provided financial support.
NSF-MRSEC provided
financial support
Grant # DMR - 0213618