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PRoteinS
ISSUE 1 | SPRING 2014
BRINGING CUTTING-EDGE SCIENCE INTO THE CLASSROOM
UNDER YOUR SKIN
Exploring proteins in your body and beyond
PRoBinG PRoteinS
A numerical look at all things protein
...
...
Uk
...
...
...
Secondary: The shape that the chain of amino acids
takes, held together by hydrogen bonds
...
...
Bangladesh
...
They give
structure to living things, carry
messages and molecules around
our bodies, support the immune
system and catalyse chemical
reactions, and they are used widely
in industry and medicine too
...
Find more resources at www
...
ac
...
Some common dietaRY SoURceS oF PRotein BY coUntRY
...
argentina
...
All figures are in grams per capita per day, 2009
...
fao
...
html
...
Other protein sources and country data available
...
Amino acid
are found in nature
Mitochondrion
Humans
Prokaryotes (e
...
bacteria)
in human proteins
Ribosome
are essential for humans
1
Go to www
...
ac
...
You can
also download the PDF of this magazine and
subscribe to the Big Picture series
...
Diameter of a hydrogen atom
online
2 | BIG PICTURE 19: PROTEINS
at least
STRUCTURE AND MOVEMENT
How proteins give structure to
organisms and help them move
SPeed oF PRotein SYntHeSiS
How manY amino acidS
...
mhhe
...
html, web
...
org/cgi-bin/protparam/
protparam1?Q8WZ42@1-34350@
Source: biowiki
...
edu/Genetics/Unit_III%3A_
The_Pathway_of_Gene_Expression/Chapter_14
...
Tensile strength (the force required to pull apart a substance), measured in megapascals (MPa)
...
wikibooks
...
ncbi
...
nih
...
Source: www
...
org/article/info:doi/10
...
pone
...
Why don’t they match?
Well, data can be interpreted in
different ways, and estimates can be
made using different methods and/or
baseline data
...
Which should you choose? The source
itself is important – is it reliable?
Are the figures recent? How might
an organisation’s ‘agenda’ affect
how it calculates and presents data?
SPRING 2014 |
StRUctURe and movement
FaSt Fact
Spider silk is a strong, naturally occurring protein
...
Source: www
...
bris
...
uk/motm/spider/page2
...
They help organisms,
cells and their contents move
...
Altogether,
around one-third of all
the protein in vertebrates is
collagen
...
In bone, for
example, calcium phosphate crystals
form in the gaps between collagen
fibres to harden it
...
diScUSS
meatY iSSUeS
Discussing protein in the diet
Meat, fish, eggs, milk and
cheese contain proteins with
broadly the same amino acid
composition as those found in
our bodies
...
If particular amino acids
are in short supply in our diet,
we can make some of them
from other molecules we eat
...
Essential amino
acids include phenylalanine
and tryptophan
...
Some plant
foods – including soya, quinoa
and hemp – contain all the
essential amino acids
...
The global appetite for it is
growing, which is putting more
pressure on food production:
feeding crops to animals is
much less efficient than eating
crops ourselves
...
The search is on for
supplements or substitutes for
meat that could help humans
to avoid eating animals, ease
pressure on cropland or simply
offer healthier alternatives –
especially to red meat, which
includes saturated fat as well
as protein
...
In 2013,
the first burger grown from
cow stem cells was cooked and
eaten
...
Questions
• Can you list three pros and
three cons of using land to
raise livestock?
• Are lab-grown burgers a
promising innovation or an
expensive diversion from
feeding the world?
• Billions of people already
eat insects regularly
...
wellcome
...
uk/
bigpicture/proteins
...
There are more than 30 different
genes for collagen in humans, and
genetic mutations can weaken the
structures supported by collagen
...
Brittle bone disease, or
‘osteogenesis imperfecta’, arises
from mutations in one type of
collagen (see ‘Real Voices’ on pages
14–15 for more on this)
...
People with Ehlers–Danlos
syndrome, which is also caused by
a range of different mutations, may
have very stretchy skin that bruises
easily and heals badly
...
Some of these problems arise
directly from changes in collagen
protein sequences
...
Those enzymes – that convert
proline to hydroxyproline or lysine
to hydroxylysine – also depend on
vitamin C
...
Leaky
capillaries cause bleeding under
the skin, teeth come loose, and
wounds no longer heal
...
Microtubules are very versatile and have
evolved to work in a range of different
ways
...
Microtubule structures are dynamic and
are constantly being built, pulled apart
and rebuilt
...
The most basic cilia move in
the ebb and flow of fluid outside the cell,
sensing changes in the environment
...
Millions of cilia
move to sweep mucus up out of the lungs
into the throat, removing inhaled dust and
dead cells
...
They
help cells move and can also be involved in
sensing the environment outside the cell
...
The sequence is GlyPro-X, where Gly is glycine, Pro is often
proline and X is usually a modified form of
proline called hydroxyproline
...
Three collagen helices
then wind round one another to form a
strong, stable collagen triple helix
...
The collagen triple helix is the most
common protein structure in the body
...
species have microtubule, cilia and flagella
proteins with very similar sequences
and secondary structures
...
In
prokaryotic cells such as bacteria, which do
not have a nuclear membrane, the flagellum
is made from a different protein called
flagellin
...
Molecular motors like this
move muscles, power cilia, shift cargo along
networks of microtubules inside the cell
and organise chromosomes for cell division
...
They are insoluble in water
...
They are found in the
tough parts of organisms, such as bones,
beaks, claws, skin, hair and feathers
...
Globular proteins include haemoglobin,
antibodies in mammals and most enzymes
...
Some proteins exist within cell
membranes
...
Conjugated proteins are those that
include non-protein parts, such as
haemoglobin
...
Shutterstock/Elnavegante
MORE ONLINE: www
...
ac
...
Source: mentalfloss
...
FocUS PRotein: HaemoGloBin
cellUlaR SiGnalS
Carries oxygen around the body
cHannellinG FailURe
Oxygen moves out of your lungs dissolved
in your blood
...
Each protein contains four haem groups, an
iron atom cradled in a ring of four nitrogen
atoms
...
Like many globular proteins, the globin
chain has stretches of alpha helix, in
which the protein chain coils around itself
under the influence of electrostatic bonds,
hydrogen bonds and van der Waals forces
between amino acid atoms
...
The way that the four subunits of
haemoglobin interact, its quaternary
structure, holds the key to its function
...
When the first iron atom takes up an
oxygen molecule in the blood capillaries
surrounding the lungs, that subunit changes
A protein problem causes cystic fibrosis
shape
...
In the tissues
that need the oxygen, the
process is reversed
...
Horse haemoglobin was the
second protein for which scientists
solved the 3D structure
...
Many
forms of haemoglobin and related
proteins have been sequenced – in
animals, plants and even bacteria
...
For more, see our animation
online (www
...
ac
...
Cystic fibrosis is one of the most common
conditions caused by a defective transport
protein
...
People who are affected
often have repeated chest infections and
problems with their digestive system
...
It
regulates the movement of chloride ions
...
The CFTR protein is large (1480 amino
acids) and almost 2000 different genetic
mutations are known
...
This removes a
single amino acid, a phenylalanine, which
is the 508th amino acid in the sequence
...
Other
mutations produce proteins that are
too short or that are present in the cell
membrane but don’t work as they should
...
g
...
Helping patients survive with
substitutes is tricky
...
Researchers are trying
to create oxygen carriers for
blood
...
Hemopure, developed in
the USA, is a preparation of cow
haemoglobin treated to make
polymers of the globin subunits
...
Other approaches include
using haemoglobin from
outdated human blood
encapsulated in an artificial
coating and making new blood
from stem cells
...
Jehovah’s
Witnesses do not accept blood
transfusions, and several owe
their lives to these substitutes
...
The
key to ‘seeing’ the complex
shapes of proteins was the
discovery that pure proteins
can be crystallised
...
When you shine a beam of
X-rays through a crystal,
the regular array of protein
molecules splits and
diverts the beam in many
directions, giving a pattern
of spots that is recorded on
a detector
...
Proteins,
with their thousands or
even tens of thousands of
atoms, presented a harder
problem that took many
years to solve
...
Transmembrane proteins,
in particular, are unstable
when purified
...
Large protein
complexes and ribosomes
can be seen using electron
microscopy
...
Computer programmes
have been developed to
do some of the work, and
scientists have tried to help
them along by incorporating
them into a computer game
that anyone can play (fold
...
These spaces
are divided by membranes studded with
proteins that control the traffic across them
...
Many straddle the
membrane, sticking out on both sides
...
Take these proteins
out of the membrane and they tend to
unravel
...
Some are pumps; they
use chemical energy to move molecules
across the membrane
...
Huge enzyme complexes that
transfer the chemical energy from food to
chemicals such as adenosine triphosphate
(ATP) are found in the mitochondria of our
cells (see pages 12–13)
...
Researchers are exploring a large group
of proteins known as G-protein-coupled
receptors
...
The receptor reads an outside signal,
usually a molecule that binds to the protein
...
This basic system is very versatile and
is involved in many things, including sight,
taste and smell, and passing on the messages
from hormones and neurotransmitters
...
The Nobel
Prize in Chemistry for 2012 was awarded for
research on these proteins
...
wellcome
...
uk/bigpicture/proteins
| BIG PICTURE 19: PROTEINS
SPRING 2014 |
deFence and SURvival
FaSt Fact
Up to 85 per cent of people with asthma are allergic to house dust
mites
...
ncbi
...
nih
...
diScUSS
UndeR attack
FocUS PRotein: immUnoGloBUlin
Scientists work to counteract some proteins’ effects
Antibodies or immunoglobulins (Ig for
short) are globular proteins, each with the
same four-chain structure – two heavy
and two light chains
...
At the
end of the antibody arms are the antigenbinding sites, variable regions that differ in
their amino acid sequence
...
They are often
proteins, and include parts of bacteria,
viruses and cells from transplanted blood
or organs
...
Each B lymphocyte
produces a specific
type of antibody
...
If an antibody
encounters an antigen that matches
it, it will bind to it, although not
as precisely as an enzyme binds to
its substrate
...
PaRt oF tHe Fold
StemminG tHe Flow
Proteins are vital for blood clotting
One of blood’s amazing properties is
that it contains a liquid toolkit that
starts the repair of blood vessels if they
spring a leak
...
These proteins unite to make
an insoluble complex, which is the
beginning of a blood clot
...
A cascade of reactions is
triggered, which leads to the activation of the enzyme thrombin from
its precursor protein prothrombin
...
Poisonous snakes often harm their
prey by interfering with blood clotting
...
Correct protein folding is essential
Everything a protein does
depends on its shape, which
itself relies on the precise
folding of the protein
chain(s)
...
But that
does not always happen
easily
...
When folding goes awry,
the results are usually bad
...
Others can lead
to accumulated ‘junk’
that eventually kills cells
...
Some of
the intermediate shapes
between the unfolded chain
and the working protein are
‘stickier’ than the desired
end product and begin
to clump together before
folding is complete
...
This switch is irreversible
because the diseased form
of the prion collects with
other prions and induces
them to convert to the
diseased form too
...
But
prion disease can also be
transmitted between people
or even between different
species, as discovered when
people ate beef products
from cows with bovine
spongiform encephalopathy
(BSE, or ‘mad cow disease’)
...
In 2011, five deaths
in the UK were caused by
variant CJD
...
Parkinson’s and Alzheimer’s
develop with age, either
because the protein clumps
grow larger or because
the machinery that helps
proteins fold properly gets
less good at its job
...
Bee venom delivers a dose
of melittin, a 26-amino-acid
peptide that inhibits several
transport proteins and enzymes
as well as attacking cell
membranes
...
The toxin is loaded into
carefully tailored nanoparticles,
which have molecular ‘bumpers’
attached
...
A
similar melittin-based system
could also have uses in treating
cancers
...
Asthma attacks, for instance,
are often triggered by proteins
found in dust mite excrement
...
A drug in development is
designed to block the enzyme
action and could prevent asthma
developing in those exposed
to the protein
...
Shutterstock/Ilya Andriyanov
USinG antiBodieS
Exploring antibodies as medicine and in research
Antibodies are made by white
blood cells called B lymphocytes
...
If you can induce
the cells to grow, they can give
you pure antibodies
...
The
hybrid cells yield monoclonal
antibodies (MAbs), which can
be produced with endlessly
different shapes
...
This can tell
you whether cells in a tissue are
making a specific protein, for
example, and even where in the
cell the protein is found
...
Other medical uses include
MAbs that block cell–surface
receptors
...
FReeZe!
Proteins stop fish from freezing
Louise Murray/Science Photo Library
Binding to unwanted invaders
Fish in the Antarctic live in salt water that
can be below normal freezing point
...
Any
ice crystals that form become coated with
this natural antifreeze and remain too
small to cause damage
...
g
...
They could
even be applied in cryonics, where people
pay to have their bodies – or sometimes
just their heads – frozen after death, in
the hope that one day medicine will be
sufficiently advanced to bring them back
to life
...
)
MORE ONLINE: www
...
ac
...
SwitcHinG SiGnalS
FocUS PRotein: inSUlin
Kinase proteins control cell processes
Regulating glucose in the blood
Insulin is a small protein hormone that
signals how much of the sugar glucose
there is in the blood
...
It was
discovered in the 1920s, and it was quickly
used to treat patients with diabetes
...
It has just 51 amino acids, arranged in
two chains linked by disulphide bonds
...
Then a large fragment of the precursor,
Hormone systems often act
through a sequence in which
the hormone binds to its
receptor on the outside of the
cell to activate the enzyme
inside the cell
...
Typically, the enzyme
involved, a kinase, adds a small
chemical group (a phosphate)
onto another protein
...
People with type 1 diabetes
make too little or no insulin
and are treated with the
hormone
...
Their treatment initially
focuses on diet
...
Some people go as far as
injecting the hormone, either to slow
ageing or to boost their fitness, even
though it is not licensed for this kind of
use in the UK
...
Questions
• What is an ‘acceptable height’ for
children who require human growth
hormone? Who should decide?
• What are the potential benefits
and risks for someone injecting
themselves with human growth
hormone to slow down ageing?
• What are the arguments for and
against the use of cow growth
hormone in dairy farming?
kinases regulate many
interactions in cells
...
BRAF is a human gene that
contains the information to
make a protein called BRAF
...
To
be active, the BRAF protein
usually requires a signal from
outside the cell
...
Some inborn mutations in
BRAF cause growth disorders
...
The skin cancer
melanoma is often associated
with BRAF mutations, for
example
...
FeelinG StUFFed
diScUSS
Growth hormone is a small soluble
protein made in the pituitary gland
in the brain and released into the
bloodstream
...
Steroid hormones are
smaller, fat-soluble molecules that
can pass through cell membranes and
usually transmit their message directly
...
Most
obviously, it promotes bone growth,
and too little or too much of it leads
to extremes of stature
...
Like insulin, growth
hormone has many other metabolic
effects
...
Humans naturally produce less
growth hormone as they age
...
This triggers the
activation of genes for defence throughout the plant
...
ncbi
...
nih
...
Pheromones carry
messages between individuals of the same
species
...
Insects often use small, volatile molecules
as pheromone messengers because they can
travel relatively long distances in the air
...
Bacteria release pheromones as an
aid to conjugation (when bacterial cells
link to transfer DNA), and many use the
concentration of particular pheromones as
an index of the local population density
...
For
example, a bacterium that lives in marine
creatures will make a glowing chemical only
when individual bacteria have detected that
there are enough other bacteria nearby for
the emitted light to be visible
...
Research suggests
that receptors in the gut, closely related
to taste receptors, register the presence
of specific food chemicals and trigger or
suppress hormone release
...
Blocking the action of
the hormone, even vaccinating against it,
might prevent obesity
...
Food intake is too important to be
left to a single hormone, and several
other messengers in the gut influence
the processing and absorption of food
...
man tHe PUmPS
Drugs can overcome mutations
in proteins
Diseases can occur when membrane
proteins function incorrectly or not at
all, and drugs often work by affecting
how these proteins function
...
In affected babies, the potassium
channels are stuck open, but
researchers found a drug that can
close the channels and trigger the
release of insulin
...
Shutterstock/Valertyn Volkov
MORE ONLINE: www
...
ac
...
Source: www
...
org
Enzymes are proteins that increase the rate of reactions, often by at least a
million times that of the uncatalysed reaction
...
True, it makes ATP, but the protein is an
impressive nanoscale machine – a complex
of proteins consisting of a transmembrane
pump and two linked motors, which rotate
...
As protons
cross the membrane, down a concentration
gradient, one motor turns, driving an axle
that turns the other and producing ATP
in the process
...
Generally, enzymes are globular proteins,
and they need the right conditions to do
their job
...
Heat denatures proteins and destroys
enzyme activity
...
The cleverest
part is that these motors can be
thrown into reverse, and ATP
can be hydrolysed to provide the
energy to pump protons against
an electrochemical gradient
...
A person
makes and recycles roughly
their body weight in ATP
every day
...
iStock
GRowinG old too Soon
BReak it down!
Meet nature’s extremophiles
The proteins that dispose of proteins
Eye of Science/Science Photo Library
withstand the freezing temperatures
of the Antarctic
...
The water bears
survive thanks to an unusually large
repertoire of heat shock proteins –
so named because they were first
discovered as part of cells’ response to
heat stress
...
Many are chaperone
proteins, which
help to stabilise
newly formed
protein
chains
...
traces of metals such as iron, magnesium,
copper and zinc in our diet
...
NAD is an
example of a cofactor, derived
from niacin (vitamin B3)
...
These ‘extremophiles’ need specially
adapted enzymes so they can carry
out essential reactions
...
One
example is the bacterium Thermus
aquaticus, first isolated from the
scalding hot springs of Yellowstone
Park
...
The polymerase chain reaction
(PCR), which is widely used in
laboratories to amplify small
samples of DNA, uses cycles of
heating and cooling to separate
and rejoin DNA double helices
...
The
answer was to use Taq polymerase
from Thermus aquaticus
...
These competitive inhibitors
can make good drugs – and poisons
...
Some contain a metal atom held inside a
stable chemical structure, such as haem in
cytochrome 450, an enzyme that detoxifies
chemicals in the liver
...
In eukaryotic organisms,
some protein degradation happens in
special bags of enzymes called lysosomes
inside the cells, and some in a big protein
complex that floats free in the cell, the
proteasome
...
The proteins destined for destruction
are tagged with a small protein named
ubiquitin, which is found in all eukaryotic
cells and has an identical sequence in all
animal species
...
There is also a more drastic process of
self-digestion: programmed cell death, or
apoptosis
...
Apoptosis is
triggered by various kinds of cell damage, as
cells can be sacrificed for the greater good of
the organism
...
g
...
Enzymes that are inactive, or
not active enough, are among
many contributors to human
ageing
...
It is seen in children with
inadequate supplies of lamin,
a fibrous protein that is vital
for maintaining the structure
of the cell nucleus
...
A major cause of progeria
is a defect in a protease that
completes the production
of lamin from its precursor,
prolamin
...
In 2013 a team of X-ray
crystallographers solved its
3D structure, explaining how
several mutations disable
the enzyme and bring on
the symptoms of one type of
progeria
...
diScUSS
well diGeSted
Digestive enzymes can be useful
We make proteins by breaking down
the ones we eat, then building new ones
from their component amino acids
...
Proteases, for
instance, hydrolyse (break) the peptide
bonds in protein
...
Several viruses,
including HIV and poliovirus, use some
of their proteases to produce finished
protein products from larger precursor
polypeptides
...
Digestive enzymes are useful in
industry
...
Biofuels are fuels
made from living matter, such as trees or
cereal crops
...
In theory, using the woody parts of
plants and crop waste would enable biofuel
to be produced without competing with
food production – and reduce carbon
dioxide emissions by being used in place of
fossil fuels
...
Questions:
• Describe three other ways that enzymes
are used in industrial settings
...
wellcome
...
uk/bigpicture/proteins
12 | BIG PICTURE 19: PROTEINS
SPRING 2014 | 1
real voices
Read an extended version of some of these interviews
at www
...
ac
...
Jack Andraka
Samantha Renke
US high school student
and scientist
What do you do?
I’m a high school student and
the inventor of a test to detect
pancreatic cancer
...
I dipped the filter
paper into a mixture of the
antibody and nanotubes, let it
dry, and repeated until there
was a coating on the paper
...
After mesothelin was applied
to the sensor, the mesothelin
bonded with the antibody and
pushed the nanotubes apart
...
Why pancreatic cancer?
When I was in middle school, a
close family friend passed away
from pancreatic cancer
...
The statistics I
found shocked me, and I was
determined to find a better way
of diagnosing the disease so
people could have the cancer
detected earlier when they
would have a better chance of
survival
...
The
process of science is the most
fun part – just testing your
hypothesis and seeing where it
leads you
...
It takes a lot
longer to get from ‘proof of
concept’ to a finished product
than I imagined!
What are you working on now?
I want to diagnose a variety
of diseases easily, quickly and
economically
...
I’m a junior in
high school so have two years
before college
...
What’s the best advice you
have?
Read widely and brainstorm
a lot! The best advice I’ve
been given is to patent your
idea before you speak about
it publicly
...
Find out more at
www
...
net
What do you do?
I used to be a language teacher,
but I am now working in
marketing and PR
...
What is brittle bone disease?
It’s a genetic disorder that
affects type I collagen in
the body and is also known
as osteogenesis imperfecta
...
Owing to multiple fractures,
people with the condition
usually have stunted growth
...
The new bone that
grows back is very weak and
can also be deformed, causing
bowing of the arms and legs
...
That can push on our
heart and lungs
...
I’ve had approximately 200
breaks in my life
...
When I
was a baby I would fracture up
to a few times a week
...
Are there any treatments?
There is no known cure,
but there are a few drugs
(bisphosphonates) that can be
taken to increase bone density
...
I’ve also got
telescopic rods in my legs to
support them and to correct
any bowing
...
If
I’m going out for drinks with
friends, I have to think: how
am I going to get there? What
happens if they don’t have a
disabled toilet? What happens
if there is a flight of stairs?
So I do have to do a lot of
planning for even the simplest
of activities
...
I’ve always been very positive
and achieved a lot in my life –
in spite of the fact that I’ve had
to battle a lot due to my health,
and because we don’t live in
a world that is designed for
disabled people
...
brittlebone
...
I hold a few British records
for my age category and for my
weight category, and I’ve competed
internationally for Great Britain and
for England
...
I also often get asked if weightlifting
is the reason I’m so small, but it’s not
...
Usually
the best shape for weightlifters is
short everything: short arms, short
legs and short body
...
Usually girls in this
class train around 50 kg and then lose
the last 2 kg over a couple of weeks
to compete
...
I’m
constantly trying to put weight on
...
The thing I eat most of
is complex carbohydrates, as that’s
what’s going to help me put on
weight, but protein straight after
training is what helps you build the
muscle once you’ve broken it down in
training
...
I’m
not really bothered about junk
food, but every single day I find
myself thinking ‘I really want some
chocolate’!
the team
How often do you train?
I train about five times a week
...
Going from being
funded and able to train twice a day
to working full time and trying to
squeeze training in around work is
quite hard – but I choose to do it
...
Women didn’t compete in the
Olympics until 2000
...
There are
women out there who are outlifting
men
...
What’s next for you?
The 2014 Commonwealth Games will
be the biggest chance I’ve ever had to
perform on the international stage,
so I’m working really hard and trying
to keep things quiet
...
britishweightlifting
...
We support the brightest
minds in biomedical research and the
medical humanities
...
We are independent of both political
and commercial interests
...
All images, unless otherwise indicated, are
from Wellcome Images
(images
...
ac
...
Big Picture is © the Wellcome Trust 2013
and is licensed under Creative Commons
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14 | BIG PICTURE 19: PROTEINS
SPRING 2014 | 15
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