5.

Beta Domains

Antiparallel -structures comprise second large group of protein domain

structures.

Functionally, this group is the most diverse;

enzymes,

transport proteins,

antibodies,

cell surface proteins,

virus coat proteins.

4 beta strands (with -loop- structure), there are 24 ways.

more beta strands, the more theoretical arrangements.

BUT!

There are only a few observed structures.

Common properties

Built up from 4 to over 10 beta strands

b strands are arranged in predominantly antiparallel fashion
The strands usually form 2 twisted sheets that are joined together
and packed against each other, resembling barrel or distorted barrel
(=double b sandwich)

4 different Domains:

Up-and-down barrel

Greek Keys

Jelly roll barrels

Beta helix domains ( quite new fold)

1) Up-and-down barrels have a simple topology

The simplest topology

successive strand is added adjacent to

the previous strand until the last strand is

joined by hydrogen bonds to the first
strand and the barrel is closed.

is similar to that in the /-barrel structures,

EXCEPT
the strands are antiparallel and all the connections are hairpins ( not alpha
helix)

adjacent beta strands in the amino

acid sequence are also adjacent in the 3D structure

Function:
transporting the lipid alcohol vitamin A (retinol) from its storage site in the
liver to vitamin-A dependent tissues
Structure:
The eight anti-parallel strands twist and curl
Two sheets packed against each other.
(green and blue, with red participating both).
A retinol molecule is bound inside the barrel, between the two sheets, such
that its only hydrophilic part (an OH tail) is at the surface of the molecule. The
binding site is lined with hydrophobic residues, which provide a hydrophobic
surrounding for the hydrophobic part of the retinol molecule.
RBP: amino acid sequence reflects structure

A large part (blue) of RBP beta strands are exposed to solvent. This is
amazingly achieved by alternating hydrophobic and hydrophilic residues in
those beta strands.

Strands 1,2,3,4,5,6 form one sheet; strands 1,8,7,6,5 form another sheet;
1,5,6 are shared.

The amino acid sequence of strands 2 3 4 of RBP clearly illustrate this

arrangement.

Membrane spanning -structures

Porin channels are made by up and down -barrels. Sixteen strands form
an antiparallel barrel that traverses the membrane. The loops at the top
of the picture are extracellular, the short turns at the bottom face the
periplasm.

A 2nd example of up-and-down b barrel: neuraminidase

Influenza virus

1. an RNA virus with an outer lipid envelope;

2. two viral proteins anchored in the membrane:

neuraminidase & hemagglutinin (both transmembrane)

Inside membrane region few residues;

transmembrane region;

Outside membrane: a stalk and a head piece

Role of hemagglutinin , will be mentioned.

Role of neuraminidase

facilitate the release of progeny virions from infected cells by

cleaving sialic acid residues from the carbohydrate side chains of the viral
hemagglutinin and of the glycosylated cellular membrane proteins

Neuraminidase

Here, up-and-down strands form six small sheets, instead of a barrel.

Each sheet has 4 strands.

The 6 sheets arranged like the blades of a 6-bladed propeller.

Loop regions between the strands form the active site in the middle of
one side of propeller.

Active sites

The 12 loops

6 connecting 6 propeller,

6 within each blade connecting 2nd and 3rd strands, form the active
site.

This is similar to the active site in the / barrel active site (on top of the
barrels formed by loops on top)
2) Greek key motif
Notice that this is not up-and-down barrel since the red strands connects from
n to n+3. They are not connected by hairpin loops. Red and green form a
Greek key motif
-crystallin as an example for greek key

Transparency and refractive power of the lenses of our eyes

Smootly changing concentration gradient of Lens specific proteinscrystallins

3) The Jelly Role

The top right picture is jelly roll motif

Then imagine you have this antiparallel beta strand, interrupted by loops.

Roll according to the jelly roll motif around the barrel, you get a jelly roll
barrel.

This is generalized Greek key

Hemagglutinin of Influenza
Like neuraminidase, hemagglutinin is another protein anchored in influenza
virus lipid envelope.
Role of hemagglutinin (glycosylated)
mediate virus binding to host cells by recognizing and binding to sialic acid
residues on glycoproteins of the cell membrane

One subunit of hemagglutinin

HA1: the first 63 residues extends 100A long, then (residues 116-261) at
the top, it forms an 8-stranded distorted jelly roll barrel. The remaining
70 residues return to the step region, running nearly antiparallel to the
initial stretch of 63 residues.

HA2: a hairpin loop of two alpha helices packed together. The second alpha
helix is 50 residue long and 76A long, goes towards the membrane.

At the bottom, there is a beta sheet of 5 antiparallel strands, with one

strand from HA1. The last 20 residues (called fusion peptide) at the
amino end of HA2 are associated with the activity by which the virus
penetrates the host cell membrane to initiate infection.

The hemagglutinin trimer

The receptor sites formed by the jelly roll domain.
To start infection, hemagglutinin binds to sialic acid residues of glycosylated
receptor proteins in the target cell surface. The virus gets into cell by
endocytosis (plasma membrane folds inward to take substances into the cell).
Antibodies in our immune system bind to this receptor binding site to prevent
the virus entering our cells
But the virus can mutate the receptor to escape this binding. This receptor is
ideal drug target.
The binding site of hemagglutinin

The binding site is located at the tip of the subunit within the jelly roll
structure.

Beta strand 1 contains a long insertion, causing a bulge in strand 8 at the

corresponding place.

Yellow ball is binding site.

A 2nd function of Hemagglutinin in the infection of host cells:

aid in endosome and viral membrane fusion

First function: binding to sialic acid residue

It binds to the plasma membrane via the receptor, and is taken into the
cells by endocytosis.

vesicles containing bound viruses causes an accumulation of protons and a

consequent lowering of the pH value inside the vesicles

hemagglutinin to change conformation due to low pH

Induce the fusion of the viral envelope membrane with the membrane of
the endosome.

Structural change at lower pH value

Hemagglutinin undergoes a massive conformational change at lower pH

value (<6).

The most obvious: HA2 straightens to form a long helix of 100A.

At lower pH value:

B becomes part of helix of 100A long, it also straightens up.

An alpha-helix region between C and D becomes loop.

The beta-hairpin E-F, and helix G all are in different places.

The large conformational change is not reversible.

The low pH form is actually more thermo-stable

3) The parallel -helix

not antiparallel

Two sheet -helix: each turn, contains 2 beta strands and 2 loop regions.
Repeated 3 times in extracellular bacterial proteinases, to form a righthanded coiled structure: two beta sheets and hydrophobic core in
between.

Each unit has 18 residues: 6 in each loop and 3 in each beta strand.
Formed by repeat of 9 residue pattern:
Gly-Gly-X-Gly-X-Asp-X-U-X
where X is any a.a., U is large & hydrophobic, often leucine.

First 6 are in loop, and later 3 are in beta strand. U from both strands
are packed inside. (remember Xs face the other side)

The loops are stabilized by having Asp binding calcium (Ca).

This 9 a.a. pattern can be used to search for such patterns.

Conclusion

The barrels act as container for diverse ligands

Diversity is due to differences in the size of the barrel and in the amino
acids that participate in formation of common core.