Alpha-Domain Structures

Alpha helices are very common in proteins.

Could a single alpha helix exist?

Single alpha helix does not have a hydrophobic core, it

is marginally stable in solution
Two (or 3,4, etc) helices can pack together and form a
hydrophobic core

Coiled coil (leucine zipper)

The simplest way to join two alpha helices

In fibrous proteins (keratin, myosin) coiled-coil
can be very long (hundreds of amino acids)
In globular proteins coiled-coils are much shorter
(~10-30 aa)

The heptad repeat

a

1 Met Lys Gln Leu Glu Asp Lys

8 Val Glu Glu Leu Leu Ser Lys
15 Asn Tyr

His Leu Glu Asn Glu

22 Val Ala Arg Leu Lys Lys Leu

d: Very often Leu (hence leucine zipper)

a: often hydrophobic
e, g: often charged
b,c,f: charged or polar
The above prefernces are strong enough to be
predicted from sequence

Why a heptad ?
1 residue (e.g-Leu some times Ile) repeats
after every 7
Hence called a HEPTAD.
Heptad provides stong indication of CCdomain structure.

Leu packs against Leu

Original concept
(zipper)

Real life

Interactions in coiled-coil

Knobs in holes model in

coiled-coil
knobs

d
a

e
holes

Leucines (knobs) of one helix sit in

hydrophobic holes of other helix

Ridges in grooves model

Helices often pack
each against other
according to Ridges
in grooves model
NOT found in coiled
coil but other motifs

Groove
Ridge

Ridge

Positions of side chains

Depending on actual
amino acid sequence,
ridges may be formed of
residues which are 3 or 4
amino acids apart

Four helix bundle

The most usual way of packing alpha
helices in globular proteins
Usually ridges in grooves model

h.pilic

h.phobic

Advantages
Marine worms(O2 transport)
Ferritin(a storage mol for iron- eukaryotes)
Human growth harmones.

Helices can be either parallel or anti

parallel in four helix bundle

Two leucine zippers can form a

four helix bundle

Leu zipper

Two helices form

leucine zipper
Two zippers pack as
ridges and grooves
Note that usually
two helices in 4hb do
not make a leu
zipper, this is just a
special case

Alpha-helical domains can be

large and complex
Bacterial
muramidase
(involved in cell
wall formation)
1domain-450 AA res

Globin fold

One of the most important structures

Present in many proteins with unrelated functions
All organisms contain proteins with globin fold
Evolved from a common ancestor
Humans: myoglobin & hemoglobin
Algae: light capturing assembly
Contains 8 helices, forming a pocket for active
site

Myoglobin
C

D
E

A
bundl of 8 hlx

Hemoglobin
Myoglobin is found in muscle cells as an internal
oxygen storage
Hemoglobin is packed in erythrocites and
transports oxygen from lungs to the rest of body
Myoglobin has a single polypeptide chain
Hemoglobin has 4 chains of two different types
nd
Both and chains have a globin fold and both
bind heme

Hemoglobin

Geometric consideration
Knobs and groove model
Ridges in rooves model.
Packing is either II or a.II at 20 b/w
helices. Some cases 50-globin fold

Globin fold-much preseved

3D structure of G.D shares common str
including mamals,insects,plant root
nodules.
Pairwise comparison shows 99%-16%
sequence homology.

Sickle-cell anemia a molecular disease

Arises, when
Glu 6 in
chains is
mutated to Val

Polymerization among hemoglobin

molecules during sickle-cell anemia
Mutated residue
6 gets inserted in
a hydrophobic
pocket of
another
hemoglobin
molecule

Mutant
hemoglobin
fibers in
erythrocytes
Mutant
Traffic jams
can be caused
in blood
vessels by
sickle shaped
erythrocites

Normal

Why is Glu 6 mutation preserved rather

than eliminated during evolution?

Mutation is predominantly found in Africa

Gives protection against malaria
Most mutation carriers are heterozygous, which have
mild symptoms of disease, but still resistant to
malaria an evolutionary advantage