Now, regulation of all three of
these proteins is very important.
The cell doesn't want
to have too much iron,
but it also doesn't want
to have too little iron.
And that regulation largely
focuses on the receptor
and on the ferritin itself by
a very interesting mechanism
that I'm going to
describe to you now.
So, both of the mechanisms for
controlling these two proteins
involve an iron response
element or IRE.
This is a structure that
appears in the messenger RNA
coding for each of
these two proteins.
This sequence forms what's
called a secondary structure
that I'll show in the messenger
RNA in just a second.
The sequence in structure
is found in the coding for
both the ferritin and the
and it's also found in some other
iron metabolizing proteins,
which tells us that again managing the
proper amounts of each of these proteins
is important just like managing their
relative amounts of iron is important.
The iron response element works
by being a target for binding
for a protein called the
IRE binding protein.
Its acronym is growing.
It's called the IRE-BP.
Now, the IRE-BP can either bind
to IREs in the messenger RNA
or it can bind to iron, but
it can't bind to both.
So the competition which one wins
the race to binds it to the IRE-BP?
The one that wins the race is the
one that's the most abundant.
If the iron concentration is high, the
IRE-BP binds to the iron, not to the IRE.
If the iron concentration is low,
the IRE-BP binds to the IRE.
Remember, the IRE is part
of the messenger RNA.
Now, as we will see, this has different
effects on these two messenger RNAs.
Well, rather than use words, let's
go look at what I'm talking about.
The iron-response element within the ferritin
messenger RNA is shown on the screen.
And we see this beautiful
that shows a duplex of basis
paired to each other.
We also see a couple of bulges and that's
characteristic of this iron-response element
and we're not exactly sure
why they're important,
but they are because we see it in virtually
every iron-response element that's there.
The ferritin messenger RNA
contains this element as I said.
On the left side of this, is the
place where the ribosome binds.
So the ribosome binding site is
the place where the ribosome
would attach itself
to the messenger RNA.
Move along this sequence,
get to the coding region,
and within the coding region,
it would read the sequence
and synthesize the
That traversing of this region
of this protein is important,
because this secondary
structure with its bulges
and potentially with the IRE-BP on it, can
stop the ribosome if the IRE-BP is there.
If the IRE-BP is not present, then the
ribosome moves through structure perfectly.
Okay. So let's take a
look at what happens.
Let's imagine first we have
a condition of low iron.
In this case, the IRE-BP, the
protein is not bound to any iron
and it's free to bind to this
IRE that we on the structure.
Here's the IRE-BP
shown in brown.
The IRE-BP binds to the ferritin
and blocks translation.
So the ribosome starts at the end
but it gets stuck because the
IRE-BP is blocking its progress.
That means translation
of ferritin is blocked.
And that means ferritin will not be made.
Now, what does that mean?
Low iron concentration turns
off ferritin production.
Why is that important?
Well, ferritin is what stores the iron.
So why make ferritin if
there's no iron to put in it.
This feedback in terms of quantity of iron
is important for managing all the
things that we've talked about so far.
Let's imagine we have
high iron concentration.
When the concentration of iron is high,
iron wins the race and binds to the IRE-BP
before the IRE-BP can bind to the IRE.
We see the iron bound to the IRE-BP.
And when that happens, the
IRE-BP cannot bind to the --
the ferritin messenger RNA, it cannot
bind the iron response element.
Consequently, the iron-response
element is left open.
The ribosome can bind with the left part,
it can traverse the secondary structure.
And it can go translate that
coding region to make ferritin.
therefore is successful.
And as a consequence of this, when
the iron concentration is high,
ferritin is synthesized
and grabs a hold of it.
This simple system allows the cell to
make the proper amount of ferritin.
Not making it when the
iron concentration is low
and making it to grab that iron when
the iron concentration is high.
The other important protein to
consider in this iron in the cell
is the the transferrin receptor.
So let's go through and
discuss that at this time.
Now, the IRE-BP you saw can bind
to the iron-response element
depending upon whether
or not iron is abundant.
It turns out in the case of the
transferrin receptor, however,
that the effect is exactly the
opposite that it was for ferritin.
Let's go through
and consider this.
Notice in the case, in which
you're seeing on the screen here,
is the messenger RNA that codes
for the transferrin receptor.
Notice in this case that the five prime end
that leads to the coding
region is completely open,
and that the IRE that's present
-- is present in five copies
and they're present at the other
end of the messenger RNA.
That means that the protection
that this offers is different
than what we saw is the case
of the ferritin messenger RNA.
When the iron concentration is high,
the IRE-BP binds to the iron.
We see that happening here.
But there's something different that's
happening with this messenger RNA
than what's happening
with the last one.
It turns out that this messenger RNA
is very sensitive to attack
by enzymes called nucleases.
Nucleases start at what's
called the three prime end
that is the right part
of this messenger RNA.
And they attack it
and move leftwards.
Well, what nucleases do is they
break down the messenger RNA.
If we have the scenario
that I've shown here
where the iron concentration is high,
the IRE-BP binds the iron and
cannot bind to those IRE elements.
The messenger RNA is
With no IRE-BP protection,
the transferrin receptor messenger RNA
gets degraded by those nucleases.
So when the iron concentration is high,
no transferrin receptor is made.
That's what we want.
If the iron concentration is high, we don’t
want receptor bringing in more transferrin.
What happens when the iron
concentration is low?
When the iron concentration is
low, the IRE-BP binds to the IRE,
not to the iron because
there's no iron to bind to.
We see that binding occurring here.
And when this occurs, the nuclease
that starts at the three prime end
gets stuck at the first IRE.
Consequently, the messenger RNA is
preserved and translation can occur.
In this case, the transferrin
receptor RNA is not degraded --
messenger RNA is not degraded and
the transferrin receptor is made.
Now, this makes very
good sense as well.
So when the iron concentration is low,
we see that the transferrin
receptor is made and translated
and this allows the cell
to bring in more iron.
This is really critical because
low concentrations of iron
are when we want
to bring iron in.
And the way in which that happens is through
action of the transferrin receptor.
In this series of lectures, I've talked
about the way in which heme itself is made,
the way in which iron is
placed into the heme,
and the way in which iron
in the body is managed
and controlled by interesting processes
relating to the iron response element
that plays roles in the translation
and the protection of messenger RNA,
of proteins involve
in iron management.