OK. I think we'll get started. We're moving into another phase of
the course today talking about cell biology. There are going to be
three lectures on cell biology covering a variety of topics.
So we've been talking about cells in
various contexts over the course of several lectures,
actually, but more or less we've talked about them as static objects
that carry out replication and transcription and translation and so
on and so forth. But, in fact, as I'm sure you are
aware, cells are highly dynamic structures which do many things at
all times. And this is a movie from which shows the movement of cells.
Cells will move randomly when you place them in a dish,
but they'll also move in a directed fashion in response to factors in
their environment that attract them or they'll move away from factors
that repel them. So cell movement is an example of a
dynamic process. Cells in the immune system,
for example, are cells that do a lot of very critical movement to get to
the site of a wound, to get to the site of an infection,
and then to elicit the proper response to that infection.
It's a late arriving crowd today. Another aspect of the dynamic
nature of cells is the fact that they divide. And I've actually
shown you this movie previously. From early embryogenesis through the
formation of the fully formed organism and then throughout adult
life, cells are receiving signals to divide at the appropriate times and
to stop dividing when it's not longer necessary.
This is a process of signal transduction, receipt of a signal
which tells the cell it's time to do something, and then to process that
signal in a way to leads to the proper cellular response.
Maybe one of the most well understood or familiar examples of
this process of signal transduction is the neuron depicted here in its
actual state filled with a dye so you can see its various processes
and diagramed here. Neurons, of course,
are part of the information transfer in the nervous system where signals
are received from these structures here called dendrites.
That signal is then propagated through the body of the neuron
through these long structures called axons and then released.
The signal finally acts upon the structures at the very end of these
nerve terminals leading to the release, for example,
of neurotransmitters. These are impressive cells for a variety of
reasons. And Professor Sive will actually give you some lectures
which deal more specifically about signaling in the nervous system.
One of the ways that they're impressive is their sheer length.
You have neurons in your body that are more than a meter in length,
and whales have neurons in their body that are tens of
meters in length. So these are remarkable cells which
carry out very specific functions. So basically what we want to talk
about over the course of today's lecture, we'll get there eventually,
we have to do some other stuff first, is the process by which cells
respond to a stimulus.
And then, much as a computer would do, to process that signal in very
sophisticated ways, which I'll introduce to you this
time and talk about in greater detail next time as well,
to lead to a particular cellular response. And I've given you three
examples of cellular responses in the movies and images this morning.
For example, the cells might respond by moving in a particular directed
fashion. They might divide because it's time for them to divide.
Or they might, in response to this signal, release a neurotransmitter
--
In the peripheral nervous system or in the brain. So what we want to
understand is what does this really mean? What are the mechanisms that
cells use to process signals? And you'll actually see analogies
to integrated circuits as we go through some examples.
Before we get there, we need to understand a little bit
about how cells are built. Largely, but not entirely,
the structure of a cell is related to its function.
So neurons are an example. Their particular structures allow
them to do the things that they do.
Erythrocytes are another example. Small red blood cells, which are
oxygen-carrying cells, are built the way they're built to
do what they need to do. And largely, but not entirely,
a cell's structure is determined by what proteins are expressed.
And also where those proteins are
found inside the cell. Where those proteins are localized
inside the cell. So I want to spend a little bit of
time talking about protein localization.
So I want to spend a little bit of time talking about protein
localization, how is it that proteins within your cells get to
where they're going, in a sense know where they're
supposed to go.
And a critical tool for understanding this process of
protein localization --
-- is fluorescence imaging.
And so I think you're all aware of standard light microscopy where you
pass white light through a sample, let's say a cell or a collection of
cells, and based on the absorbance of the light through the different
structures within those cells you're actually able to visualize what the
cells look like. With fluorescence microscopy,
what you do is shine UV light onto the cell, which brings energy to the
cell and allows molecules that will fluoresce in response to that
wavelength of UV to be visualized. So if you have a fluorescent signal
within the cell, you can see where that signal is
coming from using fluorescence microscopy or fluorescence
imaging. So how is it that we get
fluorescence from the particular structures, proteins or other things
that we want to see inside the cell? Well, there are two general ways of
doing that. The first is fluorescent antibodies.
So let's imagine we have a protein
of interest. We want to know where it is inside the cell.
And we're able to make that protein, say, in bacteria.
We can inject that protein into a bunny, that's a bunny,
or into a mouse, that's a mouse. OK. These are the common organisms
used for production of antibodies. We'll actually talk about how
antibodies are made and how they recognize the things they recognize
in subsequent lectures. But I think you all know that
antibodies are made by the body to recognize foreign stuff.
In this case, this protein that we've produced is foreign to the
bunny or to the mouse. And so in response to that it makes
an antibody, or a series of antibodies. These are proteins
which have a particular structure that we often diagram like this.
They have four chains, two big ones and two little ones. So
these are antibodies. And importantly the antibodies are
specific. That is they will bind to this protein but they won't bind to
other proteins. So they specifically recognize this
protein which is called the antigen in the context of antibodies.
We can purify these antibodies and then chemically modify them to add a
fluorochrome.
A chemical moiety that will fluoresce in response to a
particular UV wavelength of light. We can then apply those
fluorescently labeled antibodies to cells that we've put onto a glass
slide and actually poked holes in to allow the antibody to access the
inside of the cell. And then we can visualize where the
fluorescence comes from within the cell using fluorescence
imaging microscopy. So, for example,
if the protein of interest is in the nucleus, and we have labeled our
antibody with a fluorochrome that fluoresces in the green wavelength,
now when we visualize this cell by fluorescence microscopy the nucleus,
if the protein is nuclear, will look green. OK? And this has been used
in cell biology for a very long time, and it's still used today.
It's a very powerful method for determining protein localization.
This method is called immunofluorescence.
Immuno for the antibody and
fluorescence. And you can actually use multiple antibodies labeled with
different colored fluorochromes and find multiple proteins in relation
to one another. So that's one method.
To an extent, this method has been replaced by a new method which
relies on the fact that there are naturally fluorescent molecules.
Naturally fluorescent proteins,
I should say. You've actually all seen these. If you go to the beach,
you might have encountered jelly fish which fluoresce.
And they fluoresce because they make a protein which itself
fluoresces when activated by the proper UV wavelength.
These proteins have been isolated from these species,
cloned into plasmids, and then used in recombinant DNA
techniques, like I told you about before, to visualize where other
proteins go inside the cell. And I'll give you some examples of
that in a minute. But here's the jelly fish naturally.
Here are these structures. The jelly fish actually makes a
light which then causes these protein bundles to fluoresce green.
The gene was cloned, as I said. It was given the name
GFP for green fluorescence protein.
And a cDNA copy of the mRNA is used in molecular biology all over the
place to do an experiment like this. And I'll take you through an
example of another one like this in a moment where you can actually fuse
your gene of interest, gene X, cDNA corresponding to that
gene with the GFP cDNA to make a fusion protein that has your gene of
interest, plus GFP as one long polypeptide.
And now this protein will fluoresce. And you'll be able to visualize it.
And, again, I'll give you an example of how that's done in a
moment. We've also used this, we, the field has used this to make
organisms, other organisms which fluoresce.
In my lab, for example, we've mad green mice which express
the GFP protein in the cells of the skin of the mouse.
So if you shine UV light on the mouse it turns green.
It's kind of cool. And others have made pets that fluoresce.
Surprising, but true, you can actually buy a fluorescent rabbit.
I'm not sure who sells them, but they are available commercially.
And I decided to show you a picture of one, of a rabbit called Alba the
fluorescent bunny, which should be showing here.
But Alba is actually a little bit shy so she doesn't always come.
Alba the fluorescent bunny. Oh, here she comes. So this is actually
a fluorescent rabbit which was made by introducing this GFP gene into
the cells of the skin, such that it expressed in the cells
of the skin of the rabbit. So it's a very powerful technique,
but let me give you a few more examples of how it might be useful.
I know. Everybody now wants one. So if you have a cDNA for GFP,
and actually there are clever molecular engineers who have
modified this gene GFP to produce fluorescent proteins that fluoresce
in the red wavelength. So they're RFP,
red fluorescent proteins. There are yellow fluorescent
proteins. There are blue called scion CFP fluorescent proteins.
So there's a whole kit, a whole coloring box, if you will,
of different color fluorescent proteins that you can play with.
You can then add that, in techniques that you are familiar
with, to a cDNA of your gene of interest.
So this is a cDNA of your gene of
interest. If you now combine those using recombinant DNA techniques
that we told you about in previous lectures, you could make a plasmid
which has GFP fused directly in frame, to make a long open reading
frame with your gene of interest. OK? And in that plasmid you would
also include a promoter to allow the expression of this fusion.
And it's also necessary to have, at the other end, a polyadenylation
sequence, again, to insure proper expression of this
fusion protein in the cells. And this would then be housed
inside of a plasmid vector. OK? We could then transfect,
introduce, using methods similar to transformation,
but now not into bacteria. Instead into mammalian cells.
We could introduce this plasmid into cells in culture so that in the
nucleus of these cells that I've modified, I now have this new gene
present which can express a green fusion protein with my
gene of interest. Now, importantly,
the goal of this experiment is to understand where the protein that's
encoded by my gene of interest is localized. And the way that I'm
going to do that is to follow where the green color goes.
If it's a cytoplasmic protein the green will be in the cytoplasm.
If it's a nuclear protein the green will be in the nucleus and so on.
So if I now look at this cell by fluorescence microscopy,
I will see the green signal in the nucleus.
OK? It's a very, very powerful technique that allows
us to follow the products of genes of interest wherever they might go
inside of cells. And I just made a collection of
images from the literature. Here you can see, actually,
two different proteins being visualized simultaneously.
The blue is actually a DNA stain. That shows you were the nuclei are.
The green is one particular protein. And you can see that it's largely
cytoplasmic. And the red is another protein rimming the plasma membrane
of these cells. There are a whole bunch of cells
here. You can see their shape by where the red color is.
And the green is then marking the other protein which is largely
cytoplasmic. In this example, similar to what I drew on the board,
the fusion protein is in the nucleus. So the fusion protein is a nuclear
protein. It drags the GFP with it into the nucleus.
This is a structure called the endoplasmic reticulum,
the ER. We'll come back to it later in the lecture.
It's involved in the sorting of proteins to different parts of the
cell. And here's an ER protein that's been fussed to GFP.
So now the signal is coming from this structure inside the cell,
the endoplasmic reticulum. And here is a protein which resides in the
mitochondria, that energy-producing organelle inside the cell.
You can drag GFP into the mitochondria to highlight
those structures. Here's a red example,
RFP fused to a cytoskeletal protein, so you now see these long filaments
inside the cell now fluorescing red. And here's another kind of neat
example. This is a protein that moves. It's normally present in the
cytoplasm. As you can see here it's filling the cytoplasm of the cell
and it's not in the nucleus which is labeled green.
However, in response to a signal the protein moves.
It goes from the cytoplasm into the nucleus. It might be,
for example, a transcription factor, which is kept in the cytoplasm so
that it won't turn on the expression of its target genes.
But in response to the signal it now moves from the cytoplasm into the
nucleus such that it can access the DNA and begin to turn on the
expression of those genes. OK? So proteins can be followed
dynamically. And you can actually do movies of these things
over time. OK.
So proteins can be moved from place to place. How do they get there?
What is the mechanism by which proteins move from one compartment
of the cell to another? How do they know where to go?
There are two answers to this question. One is signals
in the polypeptide.
Signals within the polypeptide tell the protein where to go.
These signals can be short, a few amino acids, four, five amino
acids, they can be a little longer, 15 or 20 amino acids, but they
mostly function as a molecular zip code. They can be read by the
cell's protein sorting machinery. Like a post office reads a zip code,
it knows to send certain letters to certain places.
This machinery reads these signals and sends proteins to different
places within the cell. There's also a separate and
sometimes related mechanism --
-- known as post-translational modification.
Here it's not a sequence within the
protein amino acid sequence. It's not a signal within the amino
acid sequence, but rather it's something that's
added onto the protein after it's been made. That's why it's called
post-translational. And, again, this can influence where
the protein ends up inside the cell. So let me give you some examples of
what I'm talking about here. With respect to signals that are
contained within the polypeptide, proteins that are synthesized in the
cytoplasm on ribosomes, this is a ribosome, this is a mRNA,
5 prime end, 3 prime end, will give rise, through the process of
translation, to proteins. And when this process is completed,
those proteins will be released into the cytoplasm of the cell.
OK? Most translation occurs freely inside the cytoplasm of the cell.
There are exceptions to that, as I'll show you in a moment.
Most of it takes place freely in the cytoplasm of the cell,
so when the process is done protein winds up in the cytoplasm.
These proteins have two fates generally speaking.
One is that they remain cytoplasmic. And I gave you some examples of
cytoplasmic proteins earlier. Lots of the enzymes that are
present inside your cells just hang out inside the cytoplasm and do
their job. Other proteins are synthesized first in the cytoplasm
will end up going to the nucleus, and these proteins are
distinguishable by virtue of the fact that the ones that end up in
the nucleus have a little tag on them.
And this little tag has a name called the nuclear localization
sequence.
This is one of the short tags. It can be just four or five amino
acids, usually positively charged. And inside the cytoplasm of this
cell there are proteins which will recognize that little tag.
Attached to it these proteins belong to a class known as importins.
And what the importins do is drag the protein that has an NLS to the
nucleus where they interact with a structure within the membrane of the
nucleus known as the nuclear pore complex.
And importin then drags the protein
into the nucleus. It imports it into the nucleus.
So nuclear proteins get into the nucleus by virtue of the fact that
they have a nuclear localization sequence on them.
OK? And you might imagine, and probably you will think hard
about how you could visualize this process of nuclear importation,
for example, in a problem set. So that's how cytoplasmic resident
proteins are distinguished from nuclear proteins.
What about the proteins that fully leave the cell?
Many proteins that you make actually get secreted.
They leave the cell entirely. Still other proteins wind up on the
membrane itself. We're going to talk later in the
lecture and next time about receptors that sit on the outside of
your cell waiting for signals to be sent. Those proteins have to get
there, and there's a special mechanism that insures that.
So this applies to both secreted,
as well as what we refer to as transmembrane proteins.
And here the situation is a little
bit different. In this case, when the ribosomes
synthesize the very first few amino acids, the very first polypeptide
chain, at the end, the end terminal end of these
polypeptides, as they're emerging from the ribosome there is a longer,
more like 15 or 20 amino acid sequence known as the
signal sequence.
If a protein has a signal sequence on its end you know it's going to
end up as a secreted protein or a transmembrane protein.
And when it emerges from the bottom of the ribosome,
as depicted here, there's a specialized protein that
will bind to it, it's actually a complex of proteins
called the signal recognition particle.
SRP has a very important function,
actually two important functions. Firstly, when it binds to the
ribosome, when it binds to the signal sequence like this it leads
to translational arrest.
It stops translation. It blocks the process of
translation right at this point. OK? The next thing that happens is
that it drags this complex of the ribosome with its little nascent
polypeptide to a structure known as the endoplasmic reticulum.
In the membrane of the endoplasmic
reticulum. That was really loud. Is it that phone? I got to do this
the other day in a class. Hello. Oh, they hung up.
Last time I was teaching a class and the computer guy left his cell
phone, and it rang. And the name of the person calling
actually showed up on the screen, so I picked it up and I said Herb.
And we actually talked for about five minutes and I told him I had to
go and keep teaching a class. Anyway, inside the endoplasmic
reticulum there's another receptor, not unlike the nuclear pore complex.
This is called the SRP receptor. It binds to this thing SRP, signal
recognition particle. And this then allows SRP to go away
and allows translation to continue allowing the protein to be
synthesized through this membrane and end up inside the endoplasmic
reticulum. So the end result of this process is that the protein
will now reside within this structure, this membrane-bound
structure. Subsequently, the protein leaves
this structure in a vesicle.
It buds off the membrane, gets carried like cargo in a little
pod coming off the mother ship here. It goes to another sorting
structure called the Golgi apparatus. And it eventually goes to the
plasma membrane where it fuses to the plasma membrane allowing this
secreted protein to leave the cell. I realize that this is a little bit
messy, but there are comparable pictures in your book.
The point being that these proteins have a signal which drags them to
the ER. There's then a sorting process that takes them out of the
cell, takes them to the plasma membrane and then out of the cell.
So that's how you deal with secreted proteins.
How do you deal with proteins that end up in the membrane?
If they don't get secreted they wind up resident in the plasma
membrane. This happens by virtue of another signal.
And I'm going to pick up this process, the beginning of the
process is exactly the same. I'm going to pick up this process
at a slightly later point where we have the SRP receptor
bound by a ribosome. It's actually partway through the
process of producing a polypeptide that has wound up inside the ER.
For proteins that wind up ultimately in the membrane there's
another sequence called a stop transfer sequence.
And when a stop transfer sequence is
hit and recognized by this complex it causes the ribosome to
disassociate from the mRNA, or rather allows the synthesis to
occur without continuous transfer through this complex.
So the protein just gets built on this side of the membrane.
And the result of that then is a protein that ends up halfway in and
halfway out of the endoplasmic reticulum.
If you then take this through the sort of sorting steps that I just
outlined for secreted proteins, this protein will end up with part
of it on the outside and part of it on the inside of the cell.
OK? So that's how we deal with
proteins that are transmembrane. And you'll actually see proteins
that go through the membrane multiple times.
That's because they have signal sequences and stop transfer sequence,
signal sequences and stop transfer sequences that allow them to
transition through the membrane more than once. Many of the proteins
just once but other proteins multiple times.
OK. So that's the way it's done in terms of signal recognition.
I also mentioned that there is this
class of posttranslational modification. Proteins get modified
after they're made by translation. And the examples include
proteolysis. The protein might actually get cleaved,
cut. Half of it goes one place. The other half goes somewhere else.
Phosphorylation.
Addition of a phosphate can determine the localization of a
protein. Glycosylation. Addition of sugar groups,
carbohydrates onto the protein can determine where the protein goes.
And finally lipid addition.
Addition of a lipid molecule can determine where the protein goes.
And I'll give you one example of that last one.
A protein that we work on in my lab, the protein called RAS,
which will actually come up in the next lecture. It's a signaling
protein, which actually turns out to be very important in cancer.
In its unmodified state the protein is cytoplasmic.
However, it gets modified by an enzyme called farnesyltransferase.
Which modifies the very end of the
protein, the C terminal end of the protein, and it sticks onto it a
lipid group, about a 20 carbon lipid group, which is very much like the
fatty acid side chains in the plasma membrane.
And, in fact, this is a very hydrophobic structure.
And it ends up dragging the protein to the plasma membrane.
Here's the plasma membrane. I'm drawing it now as a lipid
bilayer, whereas I drew it as a single line previously.
And that lipid tail, which has been stuck on the RAS protein,
inserts into the lipid bilayer and localizes RAS then to the plasma
membrane. OK? So here are examples of
post-translational modifications that effect where the protein
ends up going. So we can determine where the
protein goes, that's very important. I also want to make the point
before we move onto the next topic that protein-protein interactions
are very important in determining function. These proteins that we've
been talking about almost never, probably never do their functions by
themselves. They interact with other proteins.
And these are determined, again, by sequences that bind to one
another between the two proteins. So this is actually a protein
structure from a colleague here at MIT, Thomas Schwartz,
solved by him. What you're going to look at hopefully,
this is a ribbon diagram of two proteins, the one in blue and the
one in pink. And you can see that these two proteins bind to each
other based on amino acid residues at this interface between the two
proteins. This ribbon diagram will be replaced by a space-filling model.
This is what the protein really would like inside the cell.
And here's that interface more clearly visualized with residues in
light blue on one side, pink on the other that allows the
two proteins to interact. So protein-protein interaction is
extremely important, allowing proteins to interact either
for a long time because they carry out some essential function together
or very transiently. Protein-protein interactions can be
long-lasting or very transient. And to just give you a visual
reminder of that, the transient interaction,
this I took a couple of years ago, Johnny Damon getting run into by
Damian Jackson. A very transient but actually quite
important interaction between these two baseball players.
And then there can be longer lasting interactions.
Here's Brad Pitt, well, it's not that long-lasting,
I guess, but the point is that proteins do interact either very
transiently or in a long-lasting way. Jennifer actually did the cutting
out herself of this picture that she sent me.
OK. Finally, proteins can change
their shape. Proteins can change their shape in response to binding
of other proteins or binding of cofactors that they interact with.
And here's another movie from Thomas Schwartz.
This is a signaling protein, much like the RAS protein actually.
And you'll see that upon binding to a nucleotide here,
the protein dramatically changes its shape.
It actually unwinds a little bit and exposes a new structure for binding.
And this is one of the critical ways that proteins participate in
this signal transduction, signal processing function.
They receive signals, change their shape, and this allows them to bind
to other proteins or carry out other functions. OK.
So I want to move now to the signaling introduction for the last
12 minutes or so. I started the day with this slide of
cells moving around. They're receiving signals from one
another or from the medium and they're responding to it.
I also gave you examples of cells dividing or not dividing,
cells differentiating, turning into one type of end-stage cell or
another, changing their function. We'll talk later about cells that
receive signals and kill other cells, cells that receive signals and
commit suicide in a couple of more lectures.
So cells will do very complicated things in receipt of various signals.
And this general process is known as signal transduction.
And basically it's the ability of cells to respond to things in their
extracellular environment, stimuli in their extracellular
environment. These could be physical stimuli,
light, odorants, or they could be biological stimuli,
peptides, proteins, hormones, which then get sent first from the
outside of the cell and then to the inside of the cell leading to either
short-term responses --
I'll give you an example of glucose secretion in response to a hormone
epinephrine or adrenalin. This happens exclusively inside the
cytoplasm of the cell. The signal is received,
processed, and the result is the secretion of glucose.
Other signals will make their way into the nucleus of the cell,
and this might lead to changes in gene expression.
New genes are turned. Others might be turned off.
Changes in gene expression. And this might lead to a longer
term response. And we'll give you an example of
this in the next lecture. So how does this work? Well,
it's different in every way. Each example is slightly different.
I show you this slide to give you sort of a visual picture of what
it's like, we think. Like one of these,
what do they call them, Kineto-something or rather
sculptures that you see at Logan Airport, for example,
where a small perturbation at one end is propagated through a series
of devices and leads to sounds and whistles and movements taking place
within the structure. It's not unlike dominos.
When you flip a domino at one end it can spread,
increasing its effect because of the involvement of additional dominoes
as it goes along a complex structure.
We actually found, as we were looking at the Web for
pictures of this movie of Mr. Domino, does anybody know what Mr.
Domino is? I had no idea. It's a computer game,
and they have a cool little animation which I thought I would
show you. Here's Mr. Domino. And it's actually kind of
relevant because he'll go and his signal is being transmitted along a
linear path involving other types of molecules spreading out.
Again, other types of molecules being involved,
and so on and so forth. It's not a great example but it is
kind of fun. OK. So before I give you a specific
example, I want to give you some principles about signal transduction.
And, again, the principles that are relevant here in biology are not
dissimilar to signal propagation in electrical engineering,
for example. Signal transduction in its simplest
form means that something which takes some form,
like a ligand binding to a receptor on the surface of the cell,
changes its form inside the cell. It causes a change at the membrane
to produce a different type of response inside the cell.
Importantly, for almost all of these signal transduction pathways,
what happens at the membrane is usually inadequate to change
whatever process is to be changed inside the cell such that it is
necessary for signal amplification to take place.
And we'll give you examples of how signal amplification occurs in
biology. But rather than making one square, in fact, you might
make multiple squares. There's also the opportunity,
and it's often the case for signal diversification,
so that in response to the same signal, in fact,
processed slightly different ways temporally or spatially with inside
the cell you might make, sorry, let's make this a circle.
You might make two different responses that coordinate the
overall cellular response.
There's the opportunity for what we call signal integration.
So with respect to signal
integration, you might imagine one signal which produces a particular
response. A separate signal which produces a distinct response.
But if you add the two together, that is if both signals are received
simultaneously, you get some third response.
So signal integration, again, not unlike electrical
engineering. And finally signal modulation.
So let's imagine again that we have,
in some circumstances, a particular signal giving a particular response.
If, in a different context with a different signal being received by
the cell at the same time, instead of producing this response,
there's an inhibitory effect so that nothing is produced.
This signal inhibits the processing of this signal,
so this is inhibitory. And you could imagine,
and we know exists, the opposite such that in the presence of this
signal plus now a distinct signal there's an augmentation of the
response so that now you make much more of whatever you were making.
So this is augmentation. So all of these things happen in
the process of cellular signal transduction, cellular signal
processing. At the beginning of this process, for at least the
examples we're going to talk about, things happen at the plasma membrane.
So here is the plasma membrane again.
You can think of the plasma membrane as sort of the outside of
your house with the antennas sticking up into the air waiting for
signals to be received. Well, in biological circumstances,
those antennas are polypeptide receptors. These are in this
category. Or proteins that have transmembrane domains,
get stuck in the membrane, and end up on the plasma membrane.
These polypeptide receptors are sitting out there.
There are often thousands of a given polypeptide receptor type on
the outside of a cell. And these bind to ligands that fit
inside them. There's complementarity between the shape of
the ligand and the receptor such that you get specific binding of the
ligand to the receptor. The consequences of binding of
ligand to receptor we generally think of now as changing the shape
of the receptor. Something that happens on the
outside through binding of the ligand to the receptor is propagated
through this polypeptide chain to a change in the structure at the
inside. OK? It's as though I took this guy's head and I twisted it.
Eventually his feet are going to move. The same thing here.
If I make a change out here, I can propagate that change through
the polypeptide chain and change the inside structure.
So if you imagine a ligand which has a particular structure,
I'm sorry a receptor that has a particular structure,
when you add the ligand you now change the structure.
And take a protein that might be inactive, this might have some
enzymatic activity, from inactive to one that's active.
Or another example, if I take this receptor and I bind
the ligand, change its structure, I might now allow, based on this
change in its structure, an interaction between this protein
and some other signaling molecule, some other signaling protein. And,
again, we know examples of all of those things.
Usually, maybe always,
the change that takes place at the plasma membrane,
like the first domino that you flip, doesn't have enough energy
associated with it to change the biological response.
It's necessary to propagate that signal and to amplify that signal
through various stages. This process of signal amplification
is very important. And there are two general classes
of signal amplification. One is the production of secondary
signaling molecules called second messengers. And the example that
we'll give you next time is the second messenger cyclic AMP --
-- which can be produced in large amounts following the binding of a
ligand to a receptor, thereby amplifying the signal.
And the other, which we'll give you as two examples next time,
is enzymatic, very often kinase cascades. Enzymatic cascades where
you turn on the activity of one enzyme, which turns on the activity
of more other enzymes, which turn on the activity of still
more other enzymes and so on. So, we'll talk about specifics
related to these next time.