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Hello, I'm Stephen Harrison of Harvard Medical School,
Children's Hospital Boston, and the Howard Hughes
Medical Institute. This is the first of three lectures on virus
structures. This first lecture will be about general features
of the molecular organization of virus particles. The
second two will be about specific properties of virus
particles relevant to the molecular mechanism of infecting
a cell. Viruses are carriers of genetic information from one
cell to another; in that sense, they're effectively
extracellular organelles. The infectious virus particle,
sometimes called a "virion," is a molecular machine that
packages viral genomes, escapes from the infected cell,
survives transfer from one cell to another, and attaches,
penetrates, and initiates replication in the new host cell.
It's thus not just a passive package, but rather an active
payload deliverer. Now most people know viruses as
pathogens because the virus bears the genetic
information needed to usurp the cellular biosynthetic
machinery and replicate itself. The selective advantage
for evolution of the virus may be a selective disadvantage
for the host, and as a result, hosts evolve defense
mechanisms, the immune system in the case of humans
and other higher vertebrates. Now, viruses come in two
major flavors: enveloped viruses, in which the infectious
virus particle is surrounded by a lipid bilayer membrane
derived from host cell membrane; and non-enveloped
viruses, rather unimaginatively, that have no lipid bilayer
membrane, and the protective coat is just protein. These
two structural modes correspond to different modes of exit
and entry into cells, different mechanisms of assembly,
and different mechanisms of infection, as we'll see in the
course of this lecture and the next two. Now, just as
quick examples, on the left is an example of a non-
enveloped virus particle, a rotovirus particle. This image is
based on reconstructions from many electron
micrographs, and we'll go into some of the details of that
in the third lecture. And on the other side is an example of
an enveloped virus particle, also studied by electron
microscopy, and in the cross section of the image that
you see at the bottom, you can clearly see evidence of
the lipid bilayer with α-helical segments of the protein on
the outside traversing it. Just to remind you of sizes and
distances, both the rotovirus particle and the Sindbis virus
particle, as the right-hand one was called, have outer
shells that are about 700 angstroms in diameter, or 70
nanometers. That's about a millionth the size of a tennis
ball. Recall that chemical bonds that are between one
and two angstroms in length, and that's why chemists use
angstroms rather than nanometers; it's the natural unit of a
chemical bond. So when I say 700 angstroms, you can
think of that as 500-700 atoms across. Of course it's a
volume, and so the molecular mass of these particles is
some tens of millions of daltons. So bear in mind during
this lecture the following three questions. We'll talk about
more than just these three, but the main point of the
lecture will be to try to introduce you to the following
issues. First, why most non-enveloped viruses and a
number of smaller enveloped viruses have highly
symmetric structures. Second, what do the building
blocks of these particles look like? Turns out that the
same kinds of building blocks have been used over and
over again in the evolution of different viruses, even
viruses with very different replication strategies. And
finally, what the outer proteins of some enveloped viruses
look like. So let's begin with symmetry. What does
symmetry mean? Symmetry, as suggested by the image
on the left, means that there's some operation, in the case
of physical objects some physical operation like a rotation,
that brings the object into self-coincidence. In this case, if
you rotated this figure by 120° about the axis represented
by that triangle, and you closed your eyes while you did it,
you wouldn't realize that you had done the rotation. That's
called a threefold axis, and as you can imagine, symmetry
of more complicated objects can have other symmetry
axes, and so the icosahedron (we'll come back to that in
a minute) represented on the right has fivefold axes,
threefold axes, and twofold axes of symmetry. Some
viruses have helical symmetry. Helical symmetry is
represented by a screw axis, and so tobacco mosaic
virus, which was studied historically as one of the very
first viruses for which detailed biochemistry and detailed
structure became available, is a helical array in which the
nucleic acid, the RNA, is wound into a groove on the
protein subunit and winds up with the protein, which forms
this helical array. There are a number of other helical
organizations in virus particles: Vesicular stomatitis virus is
a much more complicated enveloped virus with an outer
glycoprotein, that's what this "G" is, on the right. But as
you can imagine, helical symmetry yields elongated
particles that get unwieldy. And so far more common is
the isometric, that is, roughly spherical characteristics, of
virus particles with icosahedral symmetry. The
icosahedron, one of the Platonic solids, the fanciest one,
so to speak, with 20 triangular faces, is simply a
representation of icosahedral symmetry. An object needn't
have icosahedral shape in order to have icosahedral
symmetry. And likewise, I could destroy the symmetry of
this object by painting an asymmetric object on each
face, rather than an object with threefold symmetry. The
icosahedral symmetry is represented or characterized by,
as I said, twofold axes, fivefold axes, and threefold axes.
And if you place a single asymmetric subunit into a space
governed by icosahedral symmetry and then operate on it
with the symmetry axes, you get 59 others, that is, there
are 60 locations in all that are related to each other by
these various symmetry axes, by these various symmetry
operations. And so a particle with icosahedral symmetry
will have 60 subunits. What I've flashed in here is a sort
of schematic representation of what might be a protein
subunit, to suggest that a small particle with 60 protein
subunits appropriately interfaced with each other can form
an icosahedral structure. Now this is indeed a schematic
representation of an actual virus particle. Parvovirus is
one of the very smallest and simplest of the viruses, have
a single kind of protein subunit that forms a small shell,
and 60 of them decorate or assemble into that shell, as
suggested here. And so, if we take a slightly closer look
at that protein subunit in a traditional ribbon diagram
representing the fold of the polypeptide chain, you see
that it's based on a quite simple, compact domain
represented here in red, with large loops emanating from
it. That compact domain has this sort of fold, it's called a
"jelly roll β-barrel," or sometimes a "cupin fold," and this
particular representation comes from the structure of
canine parvovirus, a virus of dogs, as you can imagine.
But the parvovirus family includes viruses, such as adeno-
associated viruses, now being used as vectors for efforts
at gene therapy. So in this case, the simple jelly roll β-
barrel structure has been elaborated with loops in order to
make a particle of adequate size, as shown here. And
that particle can package about a 5 kilobase single-
stranded DNA genome. Since the molecular mass of the
coat protein is about 50 kilodaltons, there's just enough
volume inside to package that genome, of which about a
third is actually given over to encoding for the coat
protein. So that's a relatively expensive way of spending
your genetic information. You've got to dedicate a full
one-third just to specifying the cardboard box, if you wish,
with which you're going to deliver the payload that you
actually wish to deliver. FedEx wouldn't like a system in
which a third of the weight were in the box. So what
about trying to package larger genomes with larger
coding capacity? One example, although still by no
means as efficient as the viruses we'll start to talk about,
are the so-called picornaviruses. These are small positive-
strand RNA viruses, of which poliovirus and the human
common cold virus (human rhinoviruses) are good
examples. In this case, there are three different protein
subunits, each with one of these β jelly roll designs, very,
very similar to that red β jelly roll in the canine parvovirus,
that assemble as shown into an icosahedral structure.
And so one-sixtieth of this structure has three jelly rolls, a
red one, a blue one, and a green one, designated in that
order, VP3, VP1, and VP2, for the colors as I named
them, forming the sort of assembly that you see here.
Now, those three subunits, as I said, look strikingly like
that same β jelly roll we saw in the parvovirus subunit, but
the loops are a little less extensive, because in this case,
with three subunits, the size of the particle doesn't need
to be additionally augmented by taking up space with
those loops, and one can still package adequate
amounts of RNA. One other feature of the architecture of
this particle that's noteworthy, and we're going to see in
various forms as we look at even more complicated
viruses particles, is the nature of the interaction among
the subunits, which not only involves interfaces between
pre-folded, rigid domains of subunits, but an elaborate
inner scaffold and a little bit of an outer scaffold made by
parts of this protein's subunit that fold up only when then
particle assembles. And so on the right, you can see
some hint of this in a blow-up of VP1, VP2, and VP3,
where you can see that, in addition to the jelly roll
domains, there are extended arms, they happen to be N-
terminal and extend inward in the particle, that fold
together when the particle assembles. Now these viruses
manage to package a nine kilobase single-stranded RNA
genome, but still use about a third of the genome to
encode the coat. The same size of package can be
achieved with a single kind of subunit, if that subunit can
have multiple conformers. Why does it need to have
multiple conformers? I told you that icosahedral symmetry
requires that there be 60 and only 60 identical structures
that form an icosahedrally symmetric shell, so that if you
want to use 180 protein subunits, as in the
picornaviruses, either they have to come in three chemically distinct
kinds, three colors, if you wish, or they need to have three
distinct conformers. In this example, from a simple plant
virus called tomato bushy stunt virus, shows that indeed
one can make a very similar package with the jelly roll β-
barrels packed essentially in the same orientation and the
same packing style, so to speak, as in the picornaviruses,
but where there's only one kind of subunit, and blue, red,
and green correspond to three different conformations of
that subunit. Those conformers can be achieved by
alternate hinges between rigid domains, as shown here,
between the two different major conformations. The red
and the blue in the previous slide are actually extremely
similar to each other and would be represented by what
you see here on the right. And a second conformation not
only with a somewhat different hinge but also with an N-
terminal arm folded up in an ordered way, whereas it's
disordered and hangs into the center of the virus particle
on the other conformation. So then again one sees here
that there is an elaborate inner scaffold that dictates the
assembly formed by parts of the protein subunit that are
not rigidly folded, are not ordered, until the assembly
comes together. We can have a look at that scaffold, it's
instructive, in this blow-up of the particle by just focusing
on those 60 of the 180 subunits that have an ordered
arm. And if we now focus in on that array of protein
subunits, 60 of the 180, and look over here at where
three of them interact at a threefold axis of the
icosahedral symmetry, you see that there's an inner
scaffold formed by the N-terminal arms of the protein
subunit that dictates the size and characteristic of the
whole assembly. These arm-like extensions, which fold
together to form an inner scaffold, also form flexible links
to the RNA. This is a good example of the undemanding
packaging of a genome, as I like to call it. If the package
required either a specific nucleotide sequence for a lot of
the RNA, or a defined structure in three dimensions, let's
say, for the RNA, then the RNA could not evolve to
encode the other functions that matter: an RNA-
dependent RNA polymerase, for example. And so
packaging of nucleic acids in viruses like these involve
both a short packaging sequence or packaging signal
that is recognized by a few copies of the protein subunit
and that can act as an assembly origin; and then a large
of nonspecific, charge-neutralizing interactions to
condense the RNA into the center of the particle. And so
in the case of tomato bushy stunt virus, at the tip of the
arm is a very positively charged polypeptide segment that
condenses the RNA and neutralizes the strong negative
charge on the phosphates. The specific recognition
interactions in the case of bushy stunt virus, we don't
have a picture of, but we do have a picture of how that
same part of the arm recognizes a specific packaging
sequence in the case of a related plant virus called alfalfa
mosaic virus. And in that case, a positively charged, 25-
residue-or-so, N-terminal segment that is not well ordered
on the protein subunit as it folds on its own, co-folds with
a short packaging sequence represented here by a
standard two-dimensional sequence representation of two
stem-loops. And the three-dimensional structure
represented here leads to a specific recognition, because
the stem-loops form a defined three-dimensional
interaction stabilized by their folding together with the N-
terminal arm of a small number of subunits. Probably one
dimer is responsible for recognizing this pair of stem-loops,
and the full packaging sequence might have three such
pairs and three dimers, but the protein shell is composed
of a much larger number, and the all remaining protein
subunits will have nonspecific, positively charged,
charge-neutralizing interactions with the RNA. Now, let's
go on and talk about still larger and more complicated
virus particles. Here's a representation, a surface
representation, of a papillomavirus. Papillomaviruses
cause warts and, in some cases, cancer in humans and
many other animals. The recently introduced vaccine
against human papillomavirus 16, 18, and one or two
other types, is a vaccine that prevents transmission of the
virus, which causes cervical cancer. So this surface
representation shows you that these viruses, which
package a double-strand DNA genome, are based on an
assembly of pentameric building blocks. In this case, the
pentameric building blocks are positioned not only at
positions of fivefold symmetry in this icosahedral shell, but
also at a general nonsymmetrical position so that this
pentamer is actually surrounded by six other pentamers. A
fivefold peg in a sixfold hole, so to speak. This sort of
assembly can nonetheless be stabilized by the same sorts
of principles that we've seen in the simpler viruses,
namely, the tying together of rigid or relatively rigid building
blocks by flexible, and hence potentially multidirectional,
arms. So here the pentameric assembly of the protein L1
that forms this structure is represented here, and as you
see, there are loops coming out of it with dotted lines
here, that form the interactions between the pentamers
shown here. And of course, since this is a fivefold peg in
a sixfold hole, its arms have to be directed in different
ways, but the pentamer itself is a rigid, fivefold-symmetric
object, just like its chemically identical mate here on a
fivefold position. Now, this subunit, the L1 subunit, is also
based on the same sort of β jelly roll building block that
we saw in the positive strand RNA viruses that we were
just talking about, and it's elaborated by various loops that
vary from virus type to virus type, just one of the reasons
that these viruses come in a great variety of serotypes, of
immunologically distinct types, because these loops,
which are on the outside of the virus particle (that is, this
is the part of the pentamer that faces outward, and this is
the part that would face inward, this would be the inside
of the virus, this the outside of the virus)... these loops are
free to vary evolutionarily because they're not so critical
for the formation of the stable assembly or for forming the
rigid pentamer, and hence can respond, if you wish, to
the pressures of their coevolution with the human immune
response, or the immune response of the particular animal
that they infect. Now, a similar principle, if you wish,
namely, reuse of the same kind of building block but in
environments that don't have a simple symmetry, is
exemplified by the adenoviruses. These are even much
larger structures, and I will try to make a few points by
talking about the adenovirus structure. The particle has a
strikingly icosahedral shape with fibers coming out of the
fivefold positions that are responsible for cell attachment.
The main part of the coat is represented by a protein
called "hexon" because it forms these sorts of
hexagonally packed arrays, but in fact the hexon is not a
hexamer, it's a trimer. It's a trimer, however, with two of
these β jelly roll domains, rather similar in their overall
shape, next to each other, so it has a kind of hexagonal
outline. As a result, the face of the icosahedron does
have threefold symmetry, and the whole structure has
threefold symmetry, but the hexon itself actually is only a
threefold, and not a sixfold, symmetric entity. Now one
quite interesting aspect of the structure here is that there
is a bacteriophage called PRD1 (and indeed several
other bacteriophages now known) that has essentially
exactly the same design. Adenoviruses are viruses of
humans and vertebrates and actually a large number of
other animal species, so with this structure, one can make
the point that even viruses of bacteria have strong
resemblances in their design to those of humans and
plants, for that matter. Indeed you saw similarity between
the plant viruses, like tomato bushy stunt virus, and the
picornaviruses, such as polio and the human common
cold virus. This doesn't mean, in my own view, that these
viruses are so ancient, if you wish, in their design, in their
structure, that they antedated the divergence of bacteria
and animals, or animals and plants. Rather, we know that
viruses can jump species. They can jump from insects...
indeed, there are viruses that infect both insects and
people, and there viruses that infect both insects and
plants. And so the transfer of genetic information that I
alluded to at the very beginning of the talk, the notion that
a virus particle is package that gets genetic material from
one kind of cell to another, may well be true not just for
the cells within you or between you and another individual
of the same species, but across species. We know that
flu jumps from swine to people, as we all learned from the
2009 pandemic, or from birds to people. But also,
ultimately, through eons of time, from one kingdom to
another. At any rate, it does means that the structures
we're talking about show a striking similarity and a striking
unity, whatever the evolutionary details. In the case of the
adenoviruses, the subunit on the fivefold axis is a different
protein subunit from the hexon. It's got one β jelly roll
domain instead of two, so that again there's a kind of
duplication and elaboration as this structure develops into
a much larger shall to package, in this case, a 35
kilobase-pair, double-strand DNA genome, much, much
larger genome. And indeed there are viruses based on
very similar kinds of protein subunits, the same double jelly
roll structure with a separate, related but genetically and
chemically distinct, single jelly roll pentamer on the fivefold
axes. There are even much larger viruses based on this
kind of subunit. Now, an interesting point in relating the
adenovirus structure to the bacteriophage that I
mentioned is based on or has a similar kind of major outer
shell subunit, are the mechanisms by which the virus
forms a defined and specific structure. As you can
imagine, in this sort of structure, how in the course of
assembly is the relationship between one fivefold position
and another fivefold position determined? How is the size
of this structure determined, rather than allowing, let us
say, multiple hexons to start forming much bigger and
bigger triangles? In the case of the phage, the answer is
particularly simple. One stripped off the outer shell of
hexon-like subunits and penton-like subunits, and
discovered that, from the x-ray crystal structure of this
particle, that there is an extended protein called a "tape
measure" protein by the investigators who discovered
this, that in effect stretches from a fivefold position here to
a twofold position here and then meets another one,
twofold symmetric to the next fivefold, and that
organization, think of the scaffolds that we talked about
before, governs the fixed size of the particle. In this case,
the scaffold protein is not an arm of the same protein
subunit, it's a separate protein, but the same principle
applies, and likewise, in the adenovirus particle, there are
several different so-called "glue" or "cement" proteins
that form, in effect, a scaffold that knits together the
structure in a way that leaves no ambiguity for the size
and characteristic of the final particle. In all of these
structures, the papillomaviruses, the adenoviruses, the
picornaviruses, the plant viruses such as tomato bushy
stunt, we see a simple construction principle at work that
is a little bit like an assembly line, like a factory assembly
line. There is in all cases a fixed assembly unit, happens
to be a dimer in the case of the coat protein of TBSV.
You saw that it was a pentamer in the case of the L1
protein of the papillomaviruses. The same of the
polyomaviruses like SV40. And you saw that the
adenovirus hexon, the trimeric adenovirus hexon, is
likewise a mass-produced assembly unit. But in order to
determine how that mass-produced assembly unit fits into
a defined structure of larger size, how the positioning of
that subunit doesn't simply lead to errors in the building of
a larger or smaller particle, there's a framework or scaffold
just as in the construction of a building, let's say, that
ensures accurate placement of these mass-produced
assembly units. And we've also seen that, interestingly
enough, there's a recurring architectural motif that has
appeared in the evolution of these structures (and it's a
complicated one, so it probably evolved only once) over
and over again. Now you might well ask, is this the only
architectural motif? Why are all viruses based on a so-
similar building block, and the answer is, that isn't the
case. There's at least one other, and that sometimes is
called the "HK97" fold, after the bacteriophage HK97 in
which it was discovered. You can see that this protein
subunit looks quite different, it's got some α-helices, it's a
somewhat irregular-looking structure, and it's found in the
bacteriophage P22 and a large number of other double-
strand DNA bacteriophage, where it forms a shell with a
number of these subunits forming both hexamers and
pentamers, so that there are 60 hexamers and 12
pentamers (there are always 12 pentamers in any
icosahedral structure), as suggested here. These viruses
assemble with an inner scaffold, but the scaffold in this
case is discarded by proteolytic digestion in some cases.
In this case, it's actually reused; it exits from the particle
and gets reused in the case of P22. And the particle then
changes some details of its organization as the scaffold
exits, as part of the process by which the double-strand
DNA is injected, actually pumped, if you wish, into the
particle at the next stage in assembly. So these are cases
in which the shell preassembles around a scaffold. The
scaffold is ejected, either chewed up or literally ejected
and reused, and a series of events involving motor
proteins are responsible for inserting DNA into these
structures. Now you could ask whether this is true only of
bacteriophage, answer: "no." You might anticipate that
the answer would be no from what I told you about
adenovirus and PRD1 for example. Here are two
bacteriophage protein subunits that have this sort of
structure, but the herpesviruses, of which the ***
simplex 1, the cold sore virus, is one example, are based
on a much more elaborately looped, elaborately
decorated, version of the same fundamental fold. The
structure that we have at the moment is from electron
microscopy and not yet at the same resolution that the x-
ray structures of these subunits have yielded, but you can
probably see in this relatively low resolution representation
of the herpesvirus that this part, for example, there's a
long α-helix, corresponds to the much simpler,
undecorated fold you see here. And then these are loopy
structures that stick out and make the protein subunit
much larger and have to do with other interactions that
the protein subunit of the *** particle makes. The
herpesvirus particle is more complicated, it's both larger
and more complicated than the phage particles, and so
there are other interactions of those surface loops that are
important. Herpesviruses like the phage have very tightly
coiled DNA that is inside, that's pumped into them in this
reconstruction from electron cryomicroscopy, you can
actually see the coiling of the DNA. The DNA is actually
coiled this way, that is, circumferentially about the axis of
the particle, it's injected through one vertex, and as you
see, there's a specialized internal structure here, to which
then the tail of the phage that ultimately injects it back
into a new host cell, is attached. The cross section here
looks as if you have circumferential layers of density in the
other direction because, as you can see from this
diagram, DNA coiled about a vertical axis, if the order is
such that, from particle to particle, there isn't exactly a
piece of DNA here, but this one might be here or here,
then on average, you will get radial shells of density as
you see here, fitting tightly into the interior of the particle, I
like to say, with a gardener's analogy (it might not be
relevant for all people listening), like winding a hose into a
hose pot, or rope into a bucket. Now finally, let's talk a
little bit about enveloped viruses. Enveloped viruses
acquire their envelope, in general, their membrane (this is
not true of all enveloped viruses, but true of almost all of
them), by budding out of the cell, either out of the cell
surface, or into an intracellular compartment such as the
endoplasmic reticulum or the Golgi apparatus, and then
being transported out. And in that budding process, wrap
themselves, if you wish, in a membrane that's derived from
host cell lipids, although host cell proteins are in general
excluded. Some of the smaller enveloped viruses have
icosahedral symmetry, and their structure and assembly is
determined by regular interactions within an icosahedral
shell, just as the ones you've seen in the non-enveloped
viruses. But larger and less regular enveloped viruses are
also seen, such as *** or influenza, in which the protein
interactions are less perfect, but that doesn't matter for
protecting the nucleic acid nearly so much, because the
lipid bilayer in effect is an impermeable barrier against
agents that might get in and degrade or damage or
cleave the nucleic acid. So the budding process that I
mentioned can either involve, as in the case of the so-
called alphaviruses, or which Sindbis virus is one of the
prototypes and well studied... and a recent human
outbreak of an alphavirus is the chikungunya virus, which
had a major outbreak in the French island of Réunion,
and led to considerable interest and publicity about the
properties of that virus. The alphaviruses have a core that
preassembles in the cytoplasm and then two species of
glycoprotein that are synthesized on the rough ER,
exported to the cell surface, and then the particle buds
out through a process by which the inward-directed C-
terminal tips of the glycoprotein, which stick through the
membrane in a single α-helical segment (you might
remember very early on, I showed you a cross section
that showed that), interact one-to-one with the
icosahedrally symmetric core that's assembled rather like
a non-enveloped virus in the cytoplasm, and buds out. In
other cases, such as influenza, there's no preassembled
inner particle, but rather, the assembly occurs at the
membrane, as you see here, where the inner structures
and the glycoproteins that incorporate in the membrane
come together as part of the elaborate budding event.
Separate cellular machinery, in some cases, is then
needed to the finish the pinching off, whereas these
viruses don't seem to need a separate pinching off
mechanism. In the case of ***, these micrographs show
particularly dramatic examples of *** budding. It's
directed in this case by the interaction of the N-terminal
domain of the inner protein, the so-called "Gag" gene
product, and that protein has a myristoyl group at its N
terminus and a very positively charged surface, and
interacts with the membrane to drive budding, as shown
here. In these micrographs, you can see that the ***
particle is rather sparsely decorated with an envelope
glycoprotein that has the function of attaching the virus
particle to a new host cell and mediating viral entry. In the
case of the smaller icosahedrally symmetric enveloped
viruses, like dengue virus for example, the outer coat is
much more tightly packed, it forms a very regular array, in
case with 180 subunits of the protein whose structure is
shown up here, forming a perfect icosahedral array, and it
is an assembly of that array that drives particle budding. In
all cases of enveloped viruses, the entry process (and
that will be the topic of the next part of this set of lectures)
involves fusion of the viral membrane with a membrane of
the host cell. So just as the assembly process, the
maturation process, the exit process, involved budding
out and pinching off, so entry involves the reverse
process: attachment and fusion of the two membranes.
We'll talk about fusion in great detail in the next part of
this series, but just to give you a hint of what's to come,
an important of all of these viral envelope proteins is that,
under suitable circumstances, they can be triggered to
undergo a major conformational rearrangement. It's that
rearrangement that drives the fusion event, so that in the
case of the dengue virus particle, there is a
rearrangement from the dimeric structure shown here, a rather plate-like
organization of two somewhat elongated protein subunits,
into a trimer in which hydrophobic residues at the tip of
one of the domains, this yellow domain, so-called "domain
II," cluster together at one end of the trimer and interact
with the target cell membrane in order to begin the
process by which the two membranes are brought
together. In the case of dengue virus, this conformational
change is triggered by proton-binding, a signal that the
virus has arrived in the low pH compartment of an
endosome. In other cases, other signals are read out, so
to speak, by the fusion mechanism. We can look at this in
one more slide, where the interaction with the target cell
membrane is shown, and there is a zipping-up process of
the C-terminal part of the subunit that actually is part of
the pinching together of the two membranes, and leading
to an elaborate bit of molecular machinery. Now not all
enveloped glycoproteins form such a regular array. In the
case of the influenza virus particle, the proteins on the
surface of the virus particle sticking out from the
membrane are rather spike-like. There are two of them, as
you probably know, or two species, the hemagglutinin
and neuraminidase, the "H" and "N" of H1N1 or H5N1,
that you read about when pandemics threaten. The
hemagglutinin is the protein that undergoes a low pH-
triggered conformational rearrangement to drive fusion.
We'll be hearing quite a lot about that in the next part.
The hemagglutinin shown here is a spike-like structure as
I mentioned, its molecular design doesn't look anything
like that of the envelope protein of dengue virus, it's a
stalk-like structure, and long α-helices project the
receptor-binding site at the top about 120 or 130
angstroms away from the membrane. We'll use that
structure to discuss fusion mechanisms in much more
detail in Part 2 of this series. See you then.