Sadly, this is one of those survey clips, where
we look at a lot of different things, put names on them,
and then use that as a basis to try to figure out how things work.
So what we're going to look at are six different categories
of cytokine receptors and the ligands that they bind.
And so here we have them from left to right.
The tumor necrosis factor receptor, the immunoglobulin receptor,
the hematopoietin family receptor, sometimes
called class I, the interferon class II receptors,
the IL-17, and finally, the chemokine receptors,
which are so important in inflammation.
So here we have the tumor necrosis factor receptor.
That binds the tumor necrosis factors and ligands that
have related structures.
The one we talk about most is TNF alpha.
And there's also beta and gamma.
And there are a number of other related signalling
molecules that use a similar system.
The receptor itself, you can see, is a membrane bound receptor.
And it has four domains.
And all these little stripey things indicate
that they have lots and lots of disulphide linkages holding everything
together.
Here is what it binds to.
This is actually a juxtacrine factor.
So it doesn't really show the membrane attachment.
It often clusters in a sort of three part thing
because it's going to turn around and cluster the receptor into a trimer,
as we will see in a minute.
These are produced by monocytes and macrophages.
They're also produced by other cells.
But monocytes and macrophages are the biggies.
If you look at them, you can see they have lots of beta pleated sheets.
And here we have a picture of the TNF tripart region contacting the receptor.
And it kicks off-- well, you may not know this.
Rest in peace and FADD, which is a apoptosis trigger,
ought to clue you that this is something that leads to the death of cells.
And so interestingly enough, in addition to doing what most of these things
do-- which is to upregulate the immune system and the inflammatory response--
this, when you upregulate TNF alpha, you lose your appetite.
So this thing is involved in appetite suppression.
And over a long term, then, it actually is
responsible for something called cachexia, which is really
just a really fancy way of saying you lose weight and waste away to nothing.
So again, this is the sort of thing that you want as a short term solution
to an infection, but not as a chronic upregulator.
The next thing we have here is an immunoglobulin super family receptor.
And while most members of immunoglobulin super family
are not involved in receiving hormone or paracrine or juxtacrine signals
specifically, a few of them are.
So here, we have a slightly different way
of representing the immunoglobulin domains
with the beta pleated sheets and the disulphide linkages.
These actually have ligands that are a little less easy to characterize.
From what I can see, there are a lot of different kinds of these molecules
and a lot of different categories of signaling molecules that bind to them.
The most interesting one is something called
c-kit, which we've heard of before and may hear of again, the c-kit.
And they're all CDs for these things, too.
This is a CD117, is the actual receptor.
And it binds the c-kit ligand, which is sometimes
called stem cell factor-- that's this thing here--
or steel, or sometimes c-kit ligand.
And so again, recall that you upregulate the receptor during T cell
differentiation because this particular signal promotes cell division
while restraining, to some degree, differentiation.
And here's something that doesn't look anything like that.
This is IL-1.
It's a general upregulatory molecule for inflammation.
It binds to a different version of this.
And it has a totally different structure.
So I don't have a good story with these things.
But again, a reminder, some very important signals
are picked up by immunoglobulin receptors.
Lots of stories on this one.
This category of receptors, the hematopoietin class I receptors,
comprise the largest category of cytokine receptors
that we have studied so far.
We've found dozens of different molecules
that stimulate a variety of different versions of this molecule.
And you can see here, we're showing a trimer with three units.
This is the IL-2 receptor.
And IL-2 is one of the most critically important signals
for upregulating the immune response.
Also, we'll see that there are other ones,
like IL-4 and 5 which are important in determining a Th2 response.
There's GCSF, which is granulocyte colony stimulating factor.
So that's-- this one was named for whatever it did in some lab experiment.
But it turns out that this is important in upregulating
all kinds of immune cells in defensive responses.
There are even hematopoietin members of this family that don't even
get involved in the immune response, but they're important in prolactin.
There's a variety of different hormones, even,
that attach to this category of receptors.
Now, if you look at this one, this is a trimer.
We have three different subunits-- alpha, beta, gamma.
And this is one example, the IL-2 receptor.
Other of these receptors function as dimers.
They have two subunits.
When they're dimers, the two subunits will
be these longer ones that will resemble the beta and the gamma.
And they will have an outside receiving part and an inside signaling part.
If it's a trimer, the third part will be something
that doesn't extend into the cytoplasm and signal,
but will assist in binding whatever signal this thing binds.
So generally, when you have one of these receptors,
you can get a certain amount of response from one or two subunits by themselves.
But not until you get all two-- if it's a dimer-- or three-- if it's
a trimer-- things together will you get something
that can rouse a complete response when it binds to.
If you look at the structure of the signaling peptides in this,
you will see that each of them have at the end terminal-- that's
the one facing out-- a CCCC motif, which means conserved cysteines.
And they will have a WSXWS motif, which stands for tryptophan-- that's
the W-- serine-- that's the S. X is the whatever.
And then tryptophan serine.
And for some reason, this is a conserved motif.
And you find it in all of the molecules that also extend into the cytoplasm.
The C terminal site has a binding site, where you can put on phosphates.
And so again, if there's a third peptide, it aids to the binding,
but does not participate directly in the signaling.
Now, these guys bind to signalling molecules
that are relatively small, soluble, and have--
and you can count them-- four major alpha helices.
And this overall structure is a common theme
in pretty much all of the molecules that use this category of receptor.
As with anything else in biology, there's going to be variations
and not everything is going to be absolutely identical certainly,
or IL-2 would be IL-4, and vice versa.
But if you pull up a number of the ILs in this group-- the 2, 4, 5-- they do
have this same general overall structure.
So it's a smallish molecule.
It's soluble.
And it has four alpha helices.
And we're going to look at this one again more closely later on
and look at some of the specifics of the signalling,
because this is such an important group.
And it's a good example of how the whole system works.
Now, here is a sweet one.
It's got a heart in the middle.
This is the interferon, or class II category, of receptors.
Most of these function as heterodimers.
Sometimes there's a trimer involved in here.
But the typical mechanism is that you have two separate peptides.
And when it binds its ligand, in this case the interferon,
that will bring the two receptors together and set off a chain of signals
to the interior of the cell.
So this includes the receptor for interferon gamma, IFN gamma,
which is a major inflammatory signal.
There's also alpha and beta.
There's IL-12, which is another pro-inflammatory.
There's a dozen or more other kinds of signals.
Most of them will kick off, or support, or enhance the inflammatory response.
And again, this is another one that's so important.
We're going to look at the actual signaling pathway in detail
and as an example.
The signaling pathways, incidentally, are
common to other-- the principles are used in all kinds of cell
signaling in addition to the immune system.
So it's worth taking a bit of a close look at.
These guys also have four conserved cysteines at the end terminals,
the CCCC motif, and a cytoplasmic signaling domain,
which is involved down here.
But they don't have the WSXWS motif.
They, again, will bind to their ligand.
And the ligand will bring them together.
And that's going to recruit cytosolic tyrosine
kinases via the JAK-STAT pathway.
Again, it's a common pathway.
We're going to look at it in detail later on.
So this is another way of looking at that sort of heart shaped interferon
gamma that we had in the previous illustration.
And what we show you here is that, again, it's
a dimer, unlike the previous ligand.
And the dimer comes together.
It does have a lot of alpha helices.
That's what these barrel shaped things are.
But a big difference between this and the previous one
is that this functions as a dimer.
So it's about twice as big.
But it's also soluble.
And it can diffuse.
But it's a paracrine factor.
So it usually doesn't diffuse very far before it hits its signal.
The next category is one of, shall we say, a certain mystery.
It's the IL-17 receptor family.
And here we have an IL-17 family member.
It is a trimer.
And it's a binding two ligands up here at the top.
It's the most recently identified category of receptors.
And there are a number of structural variations in this thing
and a number of identified domains, which
is why this looks like-- looks like something you'd hang over a kid's crib,
doesn't it?
It has a lot of very interesting domains both inside and outside the cell.
Some of these exterior domains are similar to toll-like receptors.
There's this fibronectin-like domain somewhere in there.
They have variations of hetero and homodimers.
They have trimers.
And so there's a lot of variation in here.
And there's a certain amount of variation
in the categories of IL-17 paracrine factor signals.
In general, the signal molecule looks like this.
It's a small oval that's made up by putting two molecules together.
So it's a heterodimer.
It's got lots of beta pleated sheets.
You can see in here.
And you put two of them together.
And you get something that's shaped like a kind of flat egg.
And so this is the IL-17.
Now, this was first identified because there was a category of T cells,
now called the T-17 cells, that secreted this thing.
But we've also found other things secreted as well.
So the Th-17 cells are a big source of this.
And when you look at them, they kind of function
at the border of innate and adaptive immunity.
And they trigger defensive responses.
And then the other Th-1 and Th-2s come in and modulate that response
to take care of whatever threat there is.
Another interesting thing is one other cell
that secretes this is the gamma delta T cell, which are also quasi innate.
And both the Th-17 and the gamma deltas tend
to function in mucosa, or epithelia, or active border
not only of innate and adaptive, but the physical border
between you and the outside world.
Th-17 cells, we'll see, are basically seen to be primarily there
to defend you against extracellular pathogens, not intracellular ones.
So they mount a serious response, but not a scorched earth response.
And that's something we are going to go back to in just a little bit.
So this is a very, very interesting set of signals.
It's, again, a subject of very active investigation.
I don't have a really good story to tell you yet, so I'm leaving it here.
And I'm going to pick up on a few aspects of this later on.
But this is the sort of thing that I think
is really fun to follow in the literature,
because this is something where the story is unfolding.
And if you want to see the immune study in action,
this is a good thing to show how research will produce answers
that we don't currently have.
Here's the last one, the chemokine receptor.
It's a seven span receptor, the one that I sometimes
say looks like a bicycle rack.
It's got, again, an exterior exoplasmic surface
that's going to bind its ligand, which is a relatively small molecule.
It's connected up to this tripartite G-protein over here,
which it will then activate.
And in a more accurate view of its conformation,
the seven spans would be clustered together.
This being a chemokine receptor, it's important in signaling
where cells should move when there is an inflammatory or upregulated response.
So this is part of the mechanism that directs
cells to go towards an infection, or where
they need to be to fight an infection.
The chemokines that bind this are relatively small molecules.
Here, we have an example of one of them, IL-8.
Now, it's not the only thing that's a small, soluble molecule.
But what makes this one different is that you
can see it has both alpha helices and beta pleated sheets.
The beta pleated sheets are stabilized with conserved cysteines.
And this is also one where cross reception is common.
Many of the chemokines of this structure will bind to more than one
different type of receptor.
And the receptors will bind to several types of chemokines.
So there's a certain amount of cross-sensitivity
among the different chemokines.
So that's something that's an interesting thing
to explore in terms of how you can modulate and coordinate
different responses.
We're going to look at these two molecules
again, the chemokine and its receptor, in next week's lecture on inflammation.
So that was a lot of stuff.
I'm hoping you find the pictures and the outline helpful.
And that's all for now.